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  • Inverse changes in plasma tetranectin and titin levels in patients with type 2 diabetes mellitus: a potential predictor of acute myocardial infarction?
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2018-02-08
    Mohd Aizat Abdul Rahim, Zubaidah Haji Abdul Rahim, Wan Azman WAN Ahmad, Marina Mohd Bakri, Muhammad Dzafir Ismail, Onn Haji Hashim

    An early intervention using biomarkers to predict acute myocardial infarction (AMI) will effectively reduce global heart attack incidence, particularly among high-risk patients with type 2 diabetes mellitus (T2DM). This study attempted to identify potential biomarkers by detecting changes in the levels of plasma proteins in T2DM patients following onset of AMI in comparison with those without AMI. Volunteer T2DM patients without AMI (control; n=10) and T2DM patients with AMI (n=10) were recruited. Plasma samples from these patients were evaluated via two-dimensional gel electrophoresis (2DE) to screen for proteins with level changes between the two groups. The abundance of spots on gel images was analyzed using Progenesis SameSpots and subjected to false discovery rate (FDR) analysis. Protein spots with statistically significant changes of at least 1.5 fold were selected for mass spectrometry (MS) analysis. Due to strong cardiac connections, tetranectin and titin were evaluated by enzymelinked immunosorbent assay (ELISA). The adjusted P-values and fold changes between the two groups resulted in identification of 34 protein spots with significantly altered abundance. Upon MS analysis, 17 plasma proteins were identified: tetranectin, titin, clusterin, haptoglobin, myosin-13, zinc fnger protein 445, DNA repair protein RAD50, serum albumin, apolipoprotein A-IV, caspase-6, aminoacyl tRNA synthase complex-interacting multifunctional protein 1, serotransferrin, retinol-binding protein 4, transthyretin, alpha-1-antitrypsin, apolipoprotein A-I and serum amyloid A. Comparable patterns of changes in tetranectin and titin between the control and AMI groups were confirmed using ELISA. In summary, tetranectin and titin in plasma appeared to be closely associated with the onset of AMI among T2DM patients and can be used as potential biomarkers for prediction of a cardiac event, though this requires validation in a prospective cohort study.

    更新日期:2018-02-08
  • Epicatechin potentiation of glucose-stimulated insulin secretion in INS-1 cells is not dependent on its antioxidant activity
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2018-02-08
    Kaiyuan Yang, Catherine B Chan

    Epicatechin (EC) is a monomeric flavan-3-ol. We have previously demonstrated that glucose-intolerant rats fed flavan-3-ols exhibit improved pancreatic islet function corresponding with an increase in circulating EC-derived metabolites. Thus, we speculate that EC may act as a cellular signaling molecule in vivo to modulate insulin secretion. In this study we further examined the effects of different concentrations of EC on H2O2 or hyperglycemia-induced ROS production, as well as on saturated fatty acid (SFA)-impaired glucose-stimulated insulin secretion (GSIS) in INS-1 cell line in vitro. We showed that EC at a high concentration (30 μmol/L), but not a low concentration (0.3 μmol/L), significantly decreased H2O2 or hyperglycemia-induced ROS production in INS-1 cells. However, EC (0.3 μmol/L) significantly enhanced SFA-impaired GSIS in INS-1 cells. Addition of KN-93, a CaMKII inhibitor, blocked the effect of EC on insulin secretion and decreased CaMKII phosphorylation. Addition of GW1100, a GPR40 antagonist, significantly attenuated EC-enhanced GSIS, but only marginally affected CaMKII phosphorylation. These results demonstrate that EC at a physiological concentration promotes GSIS in SFA-impaired β-cells via activation of the CaMKII pathway and is consistent with its function as a GPR40 ligand. The findings support a role for EC as a cellular signaling molecule in vivo and further delineate the signaling pathways of EC in β-cells.

    更新日期:2018-02-08
  • Inhibition of the G9a/GLP histone methyltransferase complex modulates anxiety-related behavior in mice
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2018-02-08
    Dong-yao Wang, Joel Kosowan, James Samsom, Laura Leung, Kai-lai Zhang, Ying-xiang Li, Yan Xiong, Jian Jin, Arturas Petronis, Gabriel Oh, Albert H C Wong

    Epigenetic gene-regulation abnormalities have been implicated in various neuropsychiatric disorders including schizophrenia and depression, as well as in the regulation of mood and anxiety. In addition, epigenetic mechanisms are involved in the actions of psychiatric drugs. Current anxiolytic drugs have significant shortcomings, and development of new medications is warranted. Two proteins, G9a (also known as EHMT2 or KMT1C) and GLP (G9a-like protein, also known as EHMT1 or KMT1D), which methylate lysine 9 of histone H3 (H3K9), could be promising anxiolytic targets. Postnatal genetic knock-out of G9a reduces anxiety-related behavior, consistent with the reduction of G9a levels by some medications used to treat anxiety (amitriptyline, imipramine and paroxetine). Conversely, there is increased anxiety-like behavior in mice with GLP haplodeficiency. We sought to determine whether two pharmacological inhibitors of G9a/GLP, UNC0642 and A-366, would have similar effects to genetic G9a/GLP insufficiency. We found that G9a/GLP inhibition with either compound reduced anxiety-like behaviors when administered to adult mice, in conjunction with decreased H3K9 methylation in the brain. In contrast, exposure to these compounds from embryonic day 9.5 (E9.5) until birth increased anxiety-like behaviors and decreased social interaction in adulthood, while H3K9 methylation was at normal levels in the brains of the adult mice. These findings reinforce genetic evidence that G9a/GLP has different effects on anxiety-like behavior at different stages of brain development, and suggest that targeting this histone methyltransferase pathway could be useful for developing new anxiolytic drugs. These data also suggest that antidepressant exposure in utero could have negative effects in adulthood, and further investigation of these effects is warranted.

    更新日期:2018-02-08
  • Charactering the metabolism of cryptotanshinone by human P450 enzymes and uridine diphosphate glucuronosyltransferases in vitro
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2018-02-08
    Jin Zeng, Yu-juan Fan, Bo Tan, Hui-zong Su, Yue Li, Lin-lin Zhang, Jian Jiang, Fu-rong Qiu

    Cryptotanshinone (CT) is the main active component in the root of Salvia miltiorrhiza Bunge (SMB) that displays antibacterial, anti-inflammatory and anticancer activities. In this study, we characterized phase I and phase II metabolism of CT in human liver microsomes in vitro and identified the metabolic enzymes (CYPs and UGTs) involved. The metabolites of CT generated by CYPs were detected using LC-MS/MS and the CYP subtypes involved in the metabolic reactions were identified using chemical inhibitors of CYP enzymes and recombinant human CYP enzymes (CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). Glucuronidation of CT was also examined, and the UGT subtypes involved in the metabolic reactions were identified using recombinant human UGT enzymes (1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15 and 2B17). After adding NADPH to the human liver microsomes incubation system, CT was transformed into 6 main dehydrogenation and hydroxylation metabolites. CYP2A6, CYP3A4 and CYP2C19 were the major contributors to the transformation of its hydroxylation metabolites. CYP2C19, CYP1A2 and CYP3A4 were the major contributors to the transformation of its hydrogenation metabolites in human liver microsomes. This study showed that the metabolites at m/z of 473 were mediated by UGT1A9 and that the metabolites at m/z of 489 were mediated by UGT2B7 and UGT2B4. CT was extensively metabolized by UGTs following metabolism by CYPs in the liver.

    更新日期:2018-02-08
  • Different network pharmacology mechanisms of Danshen-based Fangjis in the treatment of stable angina
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2018-02-08
    Guo-xia Zhang, Ying-ying Zhang, Xiao-xu Zhang, Peng-qian Wang, Jun Liu, Qiong Liu, Zhong Wang

    Danshen (Salvia miltiorrhiza) preparations such as Danhong injection, Danshen injection, Salvianolate injection, compound Danshen injection and Sodium Tanshinone IIA Sulfonate (STS) injection are widely used in China to treat stable angina (angina pectoris) caused by coronary heart disease. In this study we compared the network pharmacological mechanisms of the 5 Danshen preparations. Following a literature search performed in PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI) database, China Biology Medicine (CBM) database, China Conference Paper Database, Wanfang Database, VIP Database and Conference Proceedings Citation Index (through January 2015), 444 randomized controlled trial publications detailing the use of the 5 Danshen-based injections for treating stable angina were identified, and their combined data were analyzed using a network meta-analysis. All of the 5 Danshen-based preparations were effective in treating stable angina with clinical improvement rates of 72.4%–91.6% and electrocardiogram (ECG) improvement rates of 54.5%–71.6%. According to both clinical improvement and ECG improvement, the 5 Danshen-based preparations were ranked as follows: Danhong injection > Salvianolate injection > STS injection > compound Danshen injection > Danshen injection. There were no significant differences among the safety profiles of the 5 Danshen preparations. The meta-analysis results were further examined using a network pharmacology approach and functional enrichment analysis, which revealed that Danshen and Danhong injections affected 4 and 15 signaling pathways, respectively, and that the 4 signaling pathways affected by Danshen were a subset of those influenced by Danhong. Therefore, Danhong injection affected some unique signaling pathways that might regulate lipoprotein metabolism, oxidation, and inflammation, and protect vascular endothelia, reflecting the multi-component and multi-target characteristics of this traditional formula and its strengths in treating complex diseases.

    更新日期:2018-02-08
  • Exosomal cargo-loading and synthetic exosome-mimics as potential therapeutic tools
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2018-02-08
    Song-pei Li, Zhong-xiao Lin, Xue-yan Jiang, Xi-yong Yu

    Exosomes are nano-sized vesicles that serve as mediators for intercellular communication through the delivery of cargo, including protein, lipids, nucleic acids or other cellular components, to neighboring or distant cells. Exosomal cargo may vary in response to different physiological or pathological conditions. The endosomal sorting complex required for transport (ESCRT) family has been widely accepted as a key mechanism in biogenesis and cargo sorting. On the other hand, accumulating evidence show that ESCRT-independent pathways exist. Due to the critical role of exosomes in intercellular communications in delivering cargo to recipient cells, exosomes have been investigated as a vector for the delivery of endogenous or exogenous cargo for therapeutic purposes. But the number of exosomes produced by cells is limited, which hampers their application. Synthetic exosome-mimics have been fabricated and investigated as a therapeutic tool for drug delivery. This review focuses on ESCRT-independent regulation of cargo loading into exosomes, including lipid raft and ceramide-mediated mechanisms, and reported exosomes or exosome-mimics with therapeutic effects.

    更新日期:2018-02-08
  • CTC clusters induced by heparanase enhance breast cancer metastasis
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2018-02-08
    Rong-rui Wei, Dan-ni Sun, Hong Yang, Juan Yan, Xiong Zhang, Xing-ling Zheng, Xu-hong Fu, Mei-yu Geng, Xun Huang, Jian Ding

    Aggregated metastatic cancer cells, referred to as circulating tumor cell (CTC) clusters, are present in the blood of cancer patients and contribute to cancer metastasis. However, the origin of CTC clusters, especially intravascular aggregates, remains unknown. Here, we employ suspension culture methods to mimic CTC cluster formation in the circulation of breast cancer patients. CTC clusters generated using these methods exhibited an increased metastatic potential that was defined by the overexpression of heparanase (HPSE). Heparanase induced FAK- and ICAM-1-dependent cell adhesion, which promoted intravascular cell aggregation. Moreover, knockdown of heparanase or inhibition of its activity with JG6, a heparanase inhibitor, was sufficient to block the formation of cell clusters and suppress breast cancer metastasis. Our data reveal that heparanase-mediated cell adhesion is critical for metastasis mediated by intravascular CTC clusters. We also suggest that targeting the function of heparanase in cancer cell dissemination might limit metastatic progression.

    更新日期:2018-02-08
  • Retraction: Probucol suppresses human glioma cell proliferation in vitro via ROS production and LKB1-AMPK activation
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2018-02-01

    Retraction: Probucol suppresses human glioma cell proliferation in vitro via ROS production and LKB1-AMPK activation Retraction: Probucol suppresses human glioma cell proliferation in vitro via ROS production and LKB1-AMPK activation, Published online: 01 February 2018; doi:10.1038/aps.2018.2 Retraction: Probucol suppresses human glioma cell proliferation in vitro via ROS production and LKB1-AMPK activation

    更新日期:2018-02-01
  • Erratum: Argonaute 2 promotes angiogenesis via the PTEN/VEGF signaling pathway in human hepatocellular carcinoma
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2018-02-01

    Erratum: Argonaute 2 promotes angiogenesis via the PTEN/VEGF signaling pathway in human hepatocellular carcinoma Erratum: Argonaute 2 promotes angiogenesis via the PTEN/VEGF signaling pathway in human hepatocellular carcinoma, Published online: 01 February 2018; doi:10.1038/aps.2018.3 Erratum: Argonaute 2 promotes angiogenesis via the PTEN/VEGF signaling pathway in human hepatocellular carcinoma

    更新日期:2018-02-01
  • Erratum: Salinomycin-loaded lipid-polymer nanoparticles with anti-CD20 aptamers selectively suppress human CD20+ melanoma stem cells
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2018-02-01

    Erratum: Salinomycin-loaded lipid-polymer nanoparticles with anti-CD20 aptamers selectively suppress human CD20+ melanoma stem cells Erratum: Salinomycin-loaded lipid-polymer nanoparticles with anti-CD20 aptamers selectively suppress human CD20+ melanoma stem cells, Published online: 01 February 2018; doi:10.1038/aps.2018.4 Erratum: Salinomycin-loaded lipid-polymer nanoparticles with anti-CD20 aptamers selectively suppress human CD20+ melanoma stem cells

    更新日期:2018-02-01
  • 3-Acetyl-oleanolic acid ameliorates non-alcoholic fatty liver disease in high fat diet-treated rats by activating AMPK-related pathways
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2018-01-18
    Qiong Ou-Yang, Chun-xiao Xuan, Xue Wang, Han-qiong Luo, Jin-E Liu, Lan-lan Wang, Ting-ting Li, Yu-peng Chen, Jun Liu

    3-Acetyl-oleanolic acid (3Ac-OA) is a derivative of oleanolic acid (OA), which has shown therapeutic beneficial effects on diabetes and metabolic syndrome. In this study we investigated whether 3Ac-OA exerted beneficial effect on non-alcoholic fatty liver disease (NAFLD) in rats and its potential underlying mechanisms. Treatment with 3Ac-OA (1–100 μmol/L) dose-dependently decreased the intracellular levels of total cholesterol (TC) and triglyceride (TG) in FFA-treated primary rat hepatocytes and human HepG2 cell lines in vitro. Furthermore, oil red staining studies showed that 3Ac-OA caused dose-dependent decrease in the number of lipid droplets in FFA-treated primary rat hepatocytes. SD rats were fed a high fat diet (HFD) for 6 weeks and subsequently treated with 3Ac-OA (60, 30, 15 mg·kg-1·d-1) for 4 weeks. 3Ac-OA administration significantly decreased the body weight, liver weight and serum TC, TG, LDL-C levels in HFD rats. Furthermore, 3AcOA administration ameliorated lipid accumulation and cell apoptosis in the liver of HFD rats. Using adipokine array analyses, we found that the levels of 11 adipokines (HGF, ICAM, IGF-1, IGFBP-3, IGFBP-5, IGFBP-6, lipocalin-2, MCP-1, M-CSF, Pref-1 and RAGE) were increased by more than twofold in the serum of 3Ac-OA-treated rats, whereas ICAM, IGF-1 and lipocalin-2 had levels increased by more than 20-fold. Moreover, 3Ac-OA administration significantly increased the expression of glucose transporter type 2 (GLUT-2) and low-density lipoprotein receptor (LDLR), as well as the phosphorylation of AMP-activated protein kinase (AMPK), protein kinase B (AKT) and glycogen synthase kinase 3β (GSK-3β) in the liver tissues of HFD rats. In conclusion, this study demonstrates that 3Ac-OA exerts a protective effect against hyperlipidemia in NAFLD rats through AMPK-related pathways.

    更新日期:2018-01-18
  • Pure mechanistic analysis of additive neuroprotective effects between baicalin and jasminoidin in ischemic stroke mice
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2018-01-18
    Peng-qian Wang, Qiong Liu, Wen-juan Xu, Ya-nan Yu, Ying-ying Zhang, Bing Li, Jun Liu, Zhong Wang

    Both baicalin (BA) and jasminoidin (JA) are active ingredients in Chinese herb medicine Scutellaria baicalensis and Fructus gardeniae, respectively. They have been shown to exert additive neuroprotective action in ischemic stroke models. In this study we used transcriptome analysis to explore the pure therapeutic mechanisms of BA, JA and their combination (BJ) contributing to phenotype variation and reversal of pathological processes. Mice with middle cerebral artery obstruction were treated with BA, JA, their combination (BJ), or concha margaritifera (CM). Cerebral infarct volume was examined to determine the effect of these compounds on phenotype. Using the hippocampus microarray and ingenuity pathway analysis (IPA) software, we exacted the differentially expressed genes, networks, pathways, and functions in positive-phenotype groups (BA, JA and BJ) by comparing with the negative-phenotype group (CM). In the BA, JA, and BJ groups, a total of 7, 4, and 11 specific target molecules, 1, 1, and 4 networks, 51, 59, and 18 canonical pathways and 70, 53, and 64 biological functions, respectively, were identified. Pure therapeutic mechanisms of BA and JA were mainly overlapped in specific target molecules, functions and pathways, which were related to the nervous system, inflammation and immune response. The specific mechanisms of BA and JA were associated with apoptosis and cancer-related signaling and endocrine and hormone regulation, respectively. In the BJ group, novel target profiles distinct from mono-therapies were revealed, including 11 specific target molecules, 10 functions, and 10 pathways, the majority of which were related to a virus-mediated immune response. The pure additive effects between BA and JA were based on enhanced action in virus-mediated immune response. This pure mechanistic analysis may provide a clearer outline of the target profiles of multi-target compounds and combination therapies.

    更新日期:2018-01-18
  • The mTOR inhibitor AZD8055 overcomes tamoxifen resistance in breast cancer cells by down-regulating HSPB8
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2018-01-18
    Jia-jie Shi, Si-meng Chen, Chen-liang Guo, Yi-xue Li, Jian Ding, Ling-hua Meng

    Tamoxifen, an important endocrine therapeutic agent, is widely used for the treatment of estrogen receptor positive (ER+) breast cancer. However, de novo or acquired resistance prevents patients from benefitting from endocrine approaches and necessitates alternative treatments. In this study, we report that small heat protein beta-8 (HSPB8) may serve as an important molecule in tamoxifen resistance. HSPB8 expression is enhanced in MCF-7 cells resistant to tamoxifen (MCF-7/R) compared to parent cells. Moreover, high expression of HSPB8 associates with poor prognosis in ER+ breast cancer patients but not in patients without classification. Stimulating ER signaling by heterogeneous expression of ERa or 17β-estradiol promotes HSPB8 expression and reduces the cell population in G1 phase. In contrast, blockage of ER signaling by tamoxifen down-regulates the expression of HSPB8. In addition, knocking down HSPB8 by specific siRNAs induces significant cell cycle arrest at G1 phase. AZD8055 was found to be more potent against the proliferation of MCF-7/R cells than that of parent cells, which was associated with down-regulation of HSPB8. We found that the anti-proliferative activity of AZD8055 was positively correlated with the HSPB8 expression level in ER+ breast cancer cells. Thus, AZD8055 was able to overcome tamoxifen resistance in breast cancer cells, and the expression of HSPB8 may predict the efficacy of AZD8055 in ER+ breast cancer. This hypothesis deserves further investigation.

    更新日期:2018-01-18
  • Ulinastatin attenuates LPS-induced inflammation in mouse macrophage RAW264.7 cells by inhibiting the JNK/NF-κB signaling pathway and activating the PI3K/Akt/Nrf2 pathway
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2018-01-11
    Si-tong Li, Qi Dai, Shu-xian Zhang, Ya-jun Liu, Qiu-qiong Yu, Fei Tan, Shu-hong Lu, Quan Wang, Jian-wen Chen, He-qing Huang, Pei-qing Liu, Min Li

    Ulinastatin (UTI) is a broad-spectrum serine protease inhibitor isolated and purified from human urine with strong anti-inflammatory and cytoprotective actions, which is widely used for the treatment of various diseases, such as pancreatitis and sepsis. Although the therapeutic effects of UTI are reported to be associated with a variety of mechanisms, the signaling pathways mediating the anti-inflammatory action of UTI remain to be elucidated. In the present study we carried out a systematic study on the anti-inflammatory and anti-oxidative mechanisms of UTI and their relationships in LPS-treated RAW264.7 cells. Pretreatment with UTI (1000 and 5000 U/mL) dose-dependently decreased the mRNA levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, iNOS) and upregulated anti-inflammatory cytokines (IL-10 and TGF-β1) in LPS-treated RAW264.7 cells. UTI pretreatment significantly inhibited the nuclear translocation of NF-κB by preventing the degradation of IκB-α. UTI pretreatment only markedly inhibited the phosphorylation of JNK at Thr183, but it did not affect the phosphorylation of JNK at Tyr185, ERK-1/2 and p38 MAPK; JNK was found to function upstream of the IκB-α/NF-κB signaling pathway. Furthermore, UTI pretreatment significantly suppressed LPS-induced ROS production by activating PI3K/Akt pathways and the nuclear translocation of Nrf2 via promotion of p62-associated Keap1 degradation. However, JNK was not involved in mediating the anti-oxidative stress effects of UTI. In summary, this study shows that UTI exerts both anti-inflammatory and anti-oxidative effects by targeting the JNK/NF-κB and PI3K/Akt/Nrf2 pathways.

    更新日期:2018-01-11
  • Tanshinol alleviates impaired bone formation by inhibiting adipogenesis via KLF15/PPARγ2 signaling in GIO rats
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2018-01-11
    Ya-jun Yang, Zhu Zhu, Dong-tao Wang, Xin-le Zhang, Yu-yu Liu, Wen-xiu Lai, Yu-lin Mo, Jin Li, Yan-long Liang, Zhuo-qing Hu, Yong-jie Yu, Liao Cui

    Glucocorticoid (GC)-induced osteoporosis (GIO) is characterized by impaired bone formation, which can be alleviated by tanshinol, an aqueous polyphenol isolated from Salvia miltiorrhiza Bunge. In this study we investigated the molecular mechanisms underlying GC-induced modulation of osteogenesis as well as the possibility of using tanshinol to interfere with GIO. Female SD rats aged 4 months were orally administered distilled water (Con), prednisone (GC, 5 mg·kg−1·d−1), GC plus tanshinol (Tan, 16 mg·kg−1·d−1) or GC plus resveratrol (Res, 5 mg·kg−1·d−1) for 14 weeks. After the rats were sacrificed, samples of bone tissues were collected. The changes in bone formation were assessed using Micro-CT, histomorphometry, and biomechanical assays. Expression of Kruppel-like factor 15 (KLF15), peroxisome proliferator-activated receptor γ 2 (PPARγ 2) and other signaling proteins in skeletal tissue was measured with Western blotting and quantitative RT-PCR. GC treatment markedly increased the expression of KLF15, PPARγ2, C/EBPα and aP2, which were related to adipogenesis, upregulated FoxO3a pathway proteins (FoxO3a and Gadd45a), and suppressed the canonical Wnt signaling (β-catenin and Axin2), which was required for osteogenesis. Thus, GC significantly decreased bone mass and bone quality. Co-treatment with Tan or Res effectively counteracted GC-impaired bone formation, suppressed GC-induced adipogenesis, and restored abnormal expression of the signaling molecules in GIO rats. We conclude that tanshinol counteracts GC-decreased bone formation by inhibiting marrow adiposity via the KLF15/PPARγ2/FoxO3a/Wnt pathway.

    更新日期:2018-01-11
  • Schisandrin ameliorates cognitive impairment and attenuates Aβ deposition in APP/PS1 transgenic mice: involvement of adjusting neurotransmitters and their metabolite changes in the brain
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2018-01-11
    Bin-bin Wei, Ming-yan Liu, Zai-xing Chen, Min-jie Wei

    Neurotransmitters (NTs) in the brain are involved in neurodegenerative diseases, such as Alzheimer's disease (AD). Schisandrin is a major ingredient of Schisandra chinensis (Turcz.) Baill and has been used for the treatment of AD. In this study we examined the therapeutic effects of schisandrin in APP/PS1 transgenic mice, and correlated the beneficial effects on cognitive impairment with the adjustments in NTs and their metabolites in the mouse brains. APP/PS1 mice were treated with schisandrin (2 mg·kg−1·d−1, ip) for 2 weeks. In Morris Water Maze test; untreated APP/PS1 mice displayed significant cognitive impairment compared with normal mice; schisandrin administration ameliorated the cognitive impairment and significantly decreased Aβ deposition in the hippocampus. In order to assess the effects of schisandrin on NTs and their metabolites, we developed a rapid and sensitive UPLC-MS/MS method for simultaneous determination of serotonin, 5-hydroxyindole acetic acid, dopamine, norepinephrine, γ-aminobutyric acid, glutamic acid, homovanillic acid, 3,4-dihydroxyphenylacetic acid and acetylcholine in mouse brains. This method conformed to methodology validation requirements. We found that there were statistically significant differences in these NTs and their metabolites between untreated APP/PS1 mice and normal mice, whereas schisandrin administration restored the abnormal NTs and their metabolites levels. These results suggest that schisandrin could alter the levels of these NTs and their metabolites in the brain, thus ameliorating learning and memory impairments in APP/PS1 mice.

    更新日期:2018-01-11
  • Regulatory T cells as a new therapeutic target for atherosclerosis
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2018-01-11
    Han-xiao Ou, Bing-bing Guo, Qi Liu, Yu-kun Li, Zhen Yang, Wen-jie Feng, Zhong-cheng Mo

    Atherosclerosis is an autoimmune disease caused by self- and non-self-antigens contributing to excessive activation of T and B cell immune responses. These responses further aggravate vascular inflammation and promote progression of atherosclerosis and vulnerability to plaques via releasing pro-inflammatory cytokines. Regulatory T cells (Tregs) as the major immunoregulatory cells, in particular, induce and maintain immune homeostasis and tolerance by suppressing the immune responses of various cells such as T and B cells, natural killer (NK) cells, monocytes, and dendritic cells (DCs), as well as by secreting inhibitory cytokines interleukin (IL)-10, IL-35 and transcription growth factor β (TGF-β) in both physiological and pathological states. Numerous evidence demonstrates that reduced numbers and dysfunction of Treg may be involveved in atherosclerosis pathogenesis. Increasing or restoring the numbers and improving the immunosuppressive capacity of Tregs may serve as a fundamental immunotherapy to treat atherosclerotic cardiovascular diseases. In this article, we briefly present current knowledge of Treg subsets, summarize the relationship between Tregs and atherosclerosis development, and discuss the possibilities of regulating Tregs for prevention of atherosclerosis pathogenesis and enhancement of plaque stability. Although the exact molecular mechanisms of Treg-mediated protection against atherosclerosis remain to be elucidated, the strategies for targeting the regulation of Tregs may provide specific and significant approaches for the prevention and treatment of atherosclerotic cardiovascular diseases.

    更新日期:2018-01-11
  • CYP3A4 inducer and inhibitor strongly affect the pharmacokinetics of triptolide and its derivative in rats
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2017-12-28
    Ye Xu, Yi-fan Zhang, Xiao-yan Chen, Da-fang Zhong

    Triptolide is the most active ingredient of Tripterygium wilfordii Hook F, which is used to treat rheumatoid arthritis. (5R)-5-Hydroxytriptolide is a hydroxylation derivative of triptolide with a reduced toxicity. To investigate the metabolic enzymes of the two compounds and the drug-drug interactions with enzyme inducers or inhibitors, a series of in vitro and in vivo experiments were conducted. In vitro studies using recombinant human cytochrome P450 enzyme demonstrated that cytochrome P450 3A4 (CYP3A4) was predominant in the metabolism of triptolide and (5R)-5-hydroxytriptolide, accounting for 94.2% and 64.2% of the metabolism, respectively. Pharmacokinetics studies were conducted in male SD rats following administration of triptolide or (5R)-5-hydroxytriptolide (0.4 mg/kg, po). The plasma exposure to triptolide and (5R)-5-hydroxytriptolide in the rats was significantly increased when co-administered with the CYP3a inhibitor ritonavir (30 mg/kg, po) with the values of AUC0–∞ (area under the plasma concentration-time curve from time zero extrapolated to infinity) being increased by 6.84 and 1.83 times, respectively. When pretreated with the CYP3a inducer dexamethasone (50 mg·kg-1·d-1, for 3 d), the AUC0–∞ values of triptolide and (5R)-5-hydroxytriptolide were decreased by 85.4% and 91.4%, respectively. These results suggest that both triptolide and (5R)-5-hydroxytriptolide are sensitive substrates of CYP3a. Because of their narrow therapeutic windows, clinical drug-drug interaction studies should be carried out to ensure their clinical medication safety and efficacy.

    更新日期:2017-12-31
  • EBP50 suppresses the proliferation of MCF-7 human breast cancer cells via promoting Beclin-1/p62-mediated lysosomal degradation of c-Myc
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2017-12-28
    Hong Liu, Wu-li Zhao, Jia-ping Wang, Bing-mu Xin, Rong-guang Shao

    c-Myc, a key activator of cell proliferation and angiogenesis, promotes the development and progression of breast cancer. Ezrin-radixin-moesin-binding phosphoprotein-50 (EBP50) is a multifunctional scaffold protein that suppresses the proliferation of breast cancer cells. In this study we investigated whether the cancer-suppressing effects of EBP50 resulted from its regulation of c-Myc signaling in human breast cancer MCF-7 cells in vitro and in vivo. We first found a significant correlation between EBP50 and c-Myc expression levels in breast cancer tissue, and demonstrated that EBP50 suppressed cell proliferation through decreasing the expression of c-Myc and its downstream proteins cyclin A, E and Cdc25A in MCF-7 cells. We further showed that EBP50 did not regulate c-Myc mRNA expression, but it promoted the degradation of c-Myc through the autophagic lysosomal pathway. Moreover, EBP50 promoted integration between c-Myc and p62, an autophagic cargo protein, triggering the autophagic lysosomal degradation of c-Myc. In EBP50-silenced MCF-7 cells, activation of autophagy by Beclin-1 promoted the degradation of c-Myc and inhibited cell proliferation. These results demonstrate that the EBP50/Beclin-1/p62/c-Myc signaling pathway plays a role in the proliferation in MCF-7 breast cancer cells: EBP50 stimulates the autophagic lysosomal degradation of c-Myc, thereby inhibits the proliferation of MCF-7 cells. Based on our results, promoting the lysosomal degradation of c-Myc might be a promising new strategy for treating breast cancer.

    更新日期:2017-12-31
  • Nucleus Accumbens, a new sleep-regulating area through the integration of motivational stimuli
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2017-12-28
    Sara Valencia Garcia, Patrice Fort

    Nucleus Accumbens, a new sleep-regulating area through the integration of motivational stimuli Nucleus Accumbens, a new sleep-regulating area through the integration of motivational stimuli, Published online: 28 December 2017; doi:10.1038/aps.2017.168 Nucleus Accumbens, a new sleep-regulating area through the integration of motivational stimuli

    更新日期:2017-12-31
  • Prefrontal AMPA receptors are involved in the effect of methylphenidate on response inhibition in rats
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2017-12-21
    Dong-dong Zhang, Yu-qiu Zhang, Xue-han Zhang

    Response inhibition is a critical executive control function in many species. Deficits in response inhibition have been observed in many disorders, eg, attention deficit/hyperactivity disorder (ADHD). The stop-signal task (SST) is a unique behavior task for evaluating response inhibition via measuring the covert latency of a stop process, and it is widely used in studies of humans, nonhuman primates and rodents. Methylphenidate (MPH; Ritalin®) is a psychostimulant that is widely used for the treatment of ADHD and that effectively improves response inhibition in individuals with ADHD and normal subjects. However, its mechanism of improving response inhibition remains unknown. In this study we adopted a rodent nose-poking version of the SST to examine response inhibition by estimating the stop signal reaction time (SSRT) in rats. Administration of MPH (1 mg/kg, sc) 25 min before the SST test exerted a baseline-dependent effect of MPH on response inhibition, ie, it shortened the SSRTs only in the rats with larger baseline SSRTs, thereby improving response inhibition in these rats. The effect of MPH on response inhibition remained 3 h after MPH administration. Co-administration of PP2 (1 mg/kg, sc), a Src-protein tyrosine kinase (Src-PTKs) inhibitor that inhibited the upregulation of glutamate receptor expression on the plasma membrane of the prefrontal cortex (PFC), abolished the MPH-caused improvement in response inhibition. Furthermore, intra-PFC infusion of a selective AMPAR antagonist.NASPM (0.3 mmol/L, per side) via stainless guide cannulas implanted earlier abolished the effect of MPH on SSRT. These results suggest that AMPA receptors in the PFC are involved in the effect of MPH on response inhibition in rats.

    更新日期:2017-12-21
  • Humanin decreases mitochondrial membrane permeability by inhibiting the membrane association and oligomerization of Bax and Bid proteins
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2017-12-21
    Ze-wei Ma, Dong-xiang Liu

    Humanin (HN) is a 24-residue peptide identified from the brain of a patient with Alzheimer's disease (AD). HN has been found to protect against neuronal insult caused by Aβ peptides or transfection of familial AD mutant genes. In order to elucidate the molecular mechanisms of HN neuroprotection, we explored the effects of HN on the association of Bax or Bid with lipid bilayers and their oligomerization in the membrane. By using single-molecule fluorescence and Förster resonance energy transfer techniques, we showed that Bax was mainly present as monomers, dimers and tetramers in lipid bilayers, while truncated Bid (tBid) enhanced the membrane association and tetramerization of Bax. HN (100 nmol/L) inhibited the self-association and tBid-activated association of Bax with the bilayers, and significantly decreased the proportion of Bax in tetramers. Furthermore, HN inhibited Bid translocation to lipid bilayers. HN could bind with Bax and Bid either in solution or in the membrane. However, HN could not pull the proteins out of the membrane. Based on these results, we propose that HN binds to Bax and cBid in solution and inhibits their translocation to the membrane. Meanwhile, HN interacts with the membrane-bound Bax and tBid, preventing the recruitment of cytosolic Bax and its oligomerization in the membrane. In this way, HN inhibits Bax pore formation in mitochondrial outer membrane and suppresses cytochrome c release and mitochondria-dependent apoptosis.

    更新日期:2017-12-21
  • Suppression of eEF-2K-mediated autophagy enhances the cytotoxicity of Raddeanin A against human breast cancer cells in vitro
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2017-12-14
    Yi-di Guan, Shi-long Jiang, Pian Yu, Mei Wen, Yi Zhang, Song-shu Xiao, Xiao-jun Xu, Yan Cheng

    Suppression of eEF-2K-mediated autophagy enhances the cytotoxicity of Raddeanin A against human breast cancer cells in vitro Suppression of eEF-2K-mediated autophagy enhances the cytotoxicity of Raddeanin A against human breast cancer cells in vitro, Published online: 14 December 2017; doi:10.1038/aps.2017.139 Suppression of eEF-2K-mediated autophagy enhances the cytotoxicity of Raddeanin A against human breast cancer cells in vitro

    更新日期:2017-12-15
  • Association of serum uric acid levels with osteoporosis and bone turnover markers in a Chinese population
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2017-12-14
    Dan-dan Yan, Jie Wang, Xu-hong Hou, Yu-qian Bao, Zhen-lin Zhang, Cheng Hu, Wei-ping Jia

    Association of serum uric acid levels with osteoporosis and bone turnover markers in a Chinese population Association of serum uric acid levels with osteoporosis and bone turnover markers in a Chinese population, Published online: 14 December 2017; doi:10.1038/aps.2017.165 Association of serum uric acid levels with osteoporosis and bone turnover markers in a Chinese population

    更新日期:2017-12-15
  • Salinomycin-loaded lipid-polymer nanoparticles with anti-CD20 aptamers selectively suppress human CD20+ melanoma stem cells
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2017-12-14
    Yi-bin Zeng, Zuo-chong Yu, Yan-ni He, Tong Zhang, Ling-bo Du, Yin-mei Dong, Huai-wen Chen, Ying-ying Zhang, Wu-qing Wang

    Salinomycin-loaded lipid-polymer nanoparticles with anti-CD20 aptamers selectively suppress human CD20+ melanoma stem cells Salinomycin-loaded lipid-polymer nanoparticles with anti-CD20 aptamers selectively suppress human CD20+ melanoma stem cells, Published online: 14 December 2017; doi:10.1038/aps.2017.166 Salinomycin-loaded lipid-polymer nanoparticles with anti-CD20 aptamers selectively suppress human CD20+ melanoma stem cells

    更新日期:2017-12-15
  • Influences of Ivabradine treatment on serum levels of cardiac biomarkers sST2, GDF-15, suPAR and H-FABP in patients with chronic heart failure
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2017-12-14
    Peter Jirak, Dzeneta Fejzic, Vera Paar, Bernhard Wernly, Rudin Pistulli, Ilonka Rohm, Christian Jung, Uta C Hoppe, P Christian Schulze, Michael Lichtenauer, Atilla Yilmaz, Daniel Kretzschmar

    Influences of Ivabradine treatment on serum levels of cardiac biomarkers sST2, GDF-15, suPAR and H-FABP in patients with chronic heart failure Influences of Ivabradine treatment on serum levels of cardiac biomarkers sST2, GDF-15, suPAR and H-FABP in patients with chronic heart failure, Published online: 14 December 2017; doi:10.1038/aps.2017.167 Influences of Ivabradine treatment on serum levels of cardiac biomarkers sST2, GDF-15, suPAR and H-FABP in patients with chronic heart failure

    更新日期:2017-12-15
  • Dendritic cell nuclear protein-1 regulates melatonin biosynthesis by binding to BMAL1 and inhibiting the transcription of N-acetyltransferase in C6 cells
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2017-12-07
    Dong Chen, Yi-pei Li, Yan-xia Yu, Tian Zhou, Chao Liu, Er-kang Fei, Feng Gao, Chen-chen Mu, Hai-gang Ren, Guang-hui Wang

    Dendritic cell nuclear protein-1 regulates melatonin biosynthesis by binding to BMAL1 and inhibiting the transcription of N-acetyltransferase in C6 cells Dendritic cell nuclear protein-1 regulates melatonin biosynthesis by binding to BMAL1 and inhibiting the transcription of N-acetyltransferase in C6 cells, Published online: 07 December 2017; doi:10.1038/aps.2017.163 Dendritic cell nuclear protein-1 regulates melatonin biosynthesis by binding to BMAL1 and inhibiting the transcription of N-acetyltransferase in C6 cells

    更新日期:2017-12-15
  • A micRNA-200c/cathepsin L feedback loop determines paclitaxel resistance in human lung cancer A549 cells in vitro through regulating epithelial–mesenchymal transition
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2017-12-07
    Yi-fan Zhao, Mei-ling Han, Ya-jie Xiong, Long Wang, Yao Fei, Xiao Shen, Ying Zhu, Zhong-qin Liang

    A micRNA-200c/cathepsin L feedback loop determines paclitaxel resistance in human lung cancer A549 cells in vitro through regulating epithelial–mesenchymal transition A micRNA-200c/cathepsin L feedback loop determines paclitaxel resistance in human lung cancer A549 cells in vitro through regulating epithelial–mesenchymal transition, Published online: 07 December 2017; doi:10.1038/aps.2017.164 A micRNA-200c/cathepsin L feedback loop determines paclitaxel resistance in human lung cancer A549 cells in vitro through regulating epithelial–mesenchymal transition

    更新日期:2017-12-15
  • C1206, a novel curcumin derivative, potently inhibits Hsp90 and human chronic myeloid leukemia cells in vitro
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2017-12-07
    Ying-juan Fan, Yi-xiang Zhou, Lian-ru Zhang, Qiao-fa Lin, Ping-zhang Gao, Fang Cai, Li-ping Zhu, Bi Liu, Jian-hua Xu

    C1206, a novel curcumin derivative, potently inhibits Hsp90 and human chronic myeloid leukemia cells in vitro C1206, a novel curcumin derivative, potently inhibits Hsp90 and human chronic myeloid leukemia cells in vitro, Published online: 07 December 2017; doi:10.1038/aps.2017.160 C1206, a novel curcumin derivative, potently inhibits Hsp90 and human chronic myeloid leukemia cells in vitro

    更新日期:2017-12-15
  • Asperosaponin VI promotes angiogenesis and accelerates wound healing in rats via up-regulating HIF-1α/VEGF signaling
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2017-12-07
    Cheng-gui Wang, Yi-ting Lou, Min-ji Tong, Li-lian Zhang, Zeng-jie Zhang, Yong-zeng Feng, Shi Li, Hua-zi Xu, Cong Mao

    Asperosaponin VI promotes angiogenesis and accelerates wound healing in rats via up-regulating HIF-1α/VEGF signaling Asperosaponin VI promotes angiogenesis and accelerates wound healing in rats via up-regulating HIF-1α/VEGF signaling, Published online: 07 December 2017; doi:10.1038/aps.2017.161 Asperosaponin VI promotes angiogenesis and accelerates wound healing in rats via up-regulating HIF-1α/VEGF signaling

    更新日期:2017-12-15
  • Exosomes: new molecular targets of diseases
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2017-12-07
    Saheli Samanta, Sheeja Rajasingh, Nicholas Drosos, Zhigang Zhou, Buddhadeb Dawn, Johnson Rajasingh

    Exosomes: new molecular targets of diseases Exosomes: new molecular targets of diseases, Published online: 07 December 2017; doi:10.1038/aps.2017.162 Exosomes: new molecular targets of diseases

    更新日期:2017-12-13
  • Pharmacokinetic and pharmacodynamic evidence for developing an oral formulation of octreotide against gastric mucosal injury
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2017-11-30
    Xi-nuo Li, Tai Rao, Yang-fan Xu, Kang-rui Hu, Zhang-pei Zhu, Hao-feng Li, Dian Kang, Yu-hao Shao, Bo-yu Shen, Xiao-xi Yin, Lin Xie, Guang-ji Wang, Yan Liang

    Pharmacokinetic and pharmacodynamic evidence for developing an oral formulation of octreotide against gastric mucosal injury Pharmacokinetic and pharmacodynamic evidence for developing an oral formulation of octreotide against gastric mucosal injury, Published online: 30 November 2017; doi:10.1038/aps.2017.159 Pharmacokinetic and pharmacodynamic evidence for developing an oral formulation of octreotide against gastric mucosal injury

    更新日期:2017-12-13
  • Activation of human smooth muscle BK channels by hydrochlorothiazide requires cell integrity and the presence of BK β1 subunit
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2017-11-30
    Pedro Martín, Melisa Moncada, Guruprasad Kuntamallappanavar, Alex M Dopico, Verónica Milesi

    Activation of human smooth muscle BK channels by hydrochlorothiazide requires cell integrity and the presence of BK β1 subunit Activation of human smooth muscle BK channels by hydrochlorothiazide requires cell integrity and the presence of BK β1 subunit, Published online: 30 November 2017; doi:10.1038/aps.2017.133 Activation of human smooth muscle BK channels by hydrochlorothiazide requires cell integrity and the presence of BK β1 subunit

    更新日期:2017-12-13
  • Capsaicin enhances the antitumor activity of sorafenib in hepatocellular carcinoma cells and mouse xenograft tumors through increased ERK signaling
    Acta Pharmacol. Sin. (IF 3.223) Pub Date : 2017-11-30
    Su-shan Zhang, Yu-hao Ni, Chen-ru Zhao, Zhen Qiao, Hong-xia Yu, Lu-yao Wang, Jin-yan Sun, Chen Du, Jia-hao Zhang, Li-ying Dong, KeWei Wang, Jian-jun Gao

    Capsaicin enhances the antitumor activity of sorafenib in hepatocellular carcinoma cells and mouse xenograft tumors through increased ERK signaling Capsaicin enhances the antitumor activity of sorafenib in hepatocellular carcinoma cells and mouse xenograft tumors through increased ERK signaling, Published online: 30 November 2017; doi:10.1038/aps.2017.156 Capsaicin enhances the antitumor activity of sorafenib in hepatocellular carcinoma cells and mouse xenograft tumors through increased ERK signaling

    更新日期:2017-12-13
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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