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Themed section: endothelin

  1. Top of page
  2. Themed section: endothelin
  3. Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer
  4. The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth
  5. ET-1 actions in the kidney: evidence for sex differences
  6. Early progress in epigenetic regulation of endothelin pathway genes
  7. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour?
  8. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans
  9. Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold
  10. Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors
  11. Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model
  12. Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis
  13. Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem
  14. Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR2) is involved in vascular function
  15. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation
  16. NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease
  17. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2
  18. Pharmacological characterization of designer cathinones in vitro
  19. Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system
  20. The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10
  21. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

主题区:内皮素

Anthony P Davenport1 and Matthias Barton2
1Clinical Pharmacology Unit, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK 2Molecular Internal Medicine, University of Zürich, Zürich, Switzerland

本期“主题区”的文章是对第12届国际内皮素会议(ET-12)以来出现的内皮素最新研究进展进行的综述。它包括内皮素-2在心血管系统、卵巢发育、免疫学和癌症中的新作用。本文讨论了内皮素对两个重要靶点的作用:心脏收缩性和生长的旁分泌和自分泌调节以及内皮素在肾病中的作用。流行病学研究表明,绝经前女性的心血管疾病患病率和内皮素-1的循环水平均低于男性;并有证据显示了性别差异在肽类反应中的作用。转录是初级水平的内皮素基因调节;本文综述了当前针对内皮素通路表观遗传调节的研究,包括肿瘤发生期间编码ETB受体的EDNRB基因的沉默。

To view the full version of this article please visit http://dx.doi.org/10.1111/bph.12022.x

查看全文请访问 http://dx.doi.org/10.1111/bph.12022.x

Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer

  1. Top of page
  2. Themed section: endothelin
  3. Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer
  4. The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth
  5. ET-1 actions in the kidney: evidence for sex differences
  6. Early progress in epigenetic regulation of endothelin pathway genes
  7. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour?
  8. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans
  9. Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold
  10. Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors
  11. Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model
  12. Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis
  13. Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem
  14. Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR2) is involved in vascular function
  15. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation
  16. NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease
  17. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2
  18. Pharmacological characterization of designer cathinones in vitro
  19. Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system
  20. The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10
  21. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

被人遗忘的异构体—内皮素-2:在心血管系统、卵巢发育、免疫学和癌症中的新作用

Lowell Ling, Janet J Maguire and Anthony P Davenport
Clinical Pharmacology Unit, University of Cambridge, Cambridge, UK

内皮素-2 [ET-2;在啮齿类动物中也叫血管活性肠收缩剂(VIC)] 与内皮素-1(ET-1)的区别是其仅有两个氨基酸,也与第三种异构体即内皮素-3(ET-3)不同,它对ETA和ETB受体的亲和性与ET-1相同。人们常常认为ET-2将模拟含量更丰富的ET-1的作用,现有用于抑制ET系统的药理学干预也能阻断ET-2的作用。出于这些猜想,人们更多地将研究重心放在ET-1上,而对ET-2的研究远没有ET-1那么详尽。最近有研究表明,我们对ET家族的理解必须重新评估。虽然ET-2在结构和药理学方面都与ET-1非常相似,并可能共存于相同的组织区间,但是有关证据一致表明ET-2是重要而独特的通路。特别是已经有研究表明ET-2在卵巢生理学中有关键作用,ET-2介导的收缩被被指出是促进排卵的最终信号。此外,ET-2也可能在心衰、免疫学和癌症中有病理生理学作用。对ET-2和ET-1的mRNA表达进行比较后表明该作用可能在基因表达水平实现,但酶类(内皮素转化酶和胃促胰酶)的肽合成方面可能存在差异,这些酶可以使这两种通路在药理学上有区别并成为各自独立的药物靶点。

To view the full version of this article please visit http://dx.doi.org/10.1111/j.1476-5381.2012.01786.x

查看全文请访问 http://dx.doi.org/10.1111/j.1476-5381.2012.01786.x

The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth

  1. Top of page
  2. Themed section: endothelin
  3. Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer
  4. The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth
  5. ET-1 actions in the kidney: evidence for sex differences
  6. Early progress in epigenetic regulation of endothelin pathway genes
  7. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour?
  8. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans
  9. Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold
  10. Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors
  11. Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model
  12. Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis
  13. Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem
  14. Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR2) is involved in vascular function
  15. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation
  16. NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease
  17. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2
  18. Pharmacological characterization of designer cathinones in vitro
  19. Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system
  20. The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10
  21. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

旁分泌/自分泌介质内皮素-1对心肌收缩性和生长调节的作用

Faye M Drawnel1, Caroline R Archer1 and H Llewelyn Roderick1,2
1Babraham Research Campus, Babraham Institute, Cambridge, UK, and 2Department of Pharmacology, University of Cambridge, Cambridge, UK

内皮素-1(ET-1)是心肌生理学和病理学的关键性自分泌和旁分泌调节因子。由于各种机械和神经激素刺激而在心肌中局部产生的ET-1能急性调节心肌收缩性。在发生诸如缺血、左心室肥大和心衰等病理性心血管疾病期间,肌细胞表达和整体ET-1系统的活性会增强,使这种肽既能启动也能维持不适应的细胞反应。ET-1的急性和慢性作用都依赖于细胞内信号通路的激活,受ETA受体激活时产生的三磷酸肌醇和甘油二酯的调节。随后对蛋白激酶C和D、钙调蛋白依赖性激酶II、钙神经素(calcineurin)和MAPKs的刺激可改变收缩期钙瞬变、肌原纤维功能和协调细胞重塑的转录因子的活性。ET-1细胞反应的确切性质取决于这种信号的时间、定位和环境,从而使这种肽能调节心肌细胞的生理学和诱发疾病。

To view the full version of this article please visit http://dx.doi.org/10.1111/j.1476-5381.2012.02195.x

查看全文请访问 http://dx.doi.org/10.1111/j.1476-5381.2012.02195.x

ET-1 actions in the kidney: evidence for sex differences

  1. Top of page
  2. Themed section: endothelin
  3. Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer
  4. The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth
  5. ET-1 actions in the kidney: evidence for sex differences
  6. Early progress in epigenetic regulation of endothelin pathway genes
  7. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour?
  8. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans
  9. Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold
  10. Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors
  11. Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model
  12. Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis
  13. Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem
  14. Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR2) is involved in vascular function
  15. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation
  16. NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease
  17. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2
  18. Pharmacological characterization of designer cathinones in vitro
  19. Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system
  20. The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10
  21. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

ET-1在肾内的作用:性别差异的证据

W Kittikulsuth, JC Sullivan and DM Pollock
Experimental Medicine, Department of Medicine, Georgia Health Sciences University, Augusta, GA, USA

高血压和慢性肾病在男性中比在同龄的绝经前女性中更为常见。在动物模型中产生高血压或肾损伤的遗传或药理学程序中,雌性动物的损伤程度相对更低。内皮素(ET)系统的过度激活或功能障碍可以调节高血压或肾病的进程,其中ETA受体的作用主要是介导血管收缩、损伤和抗尿钠排泄,ETB受体的作用则正好相反。本综述的目的是考查ET系统在肾脏中的作用,重点分析与高血压和肾病的易感性和进程相关的性别差异。在大部分的动物模型中,雄性动物都有更高的肾ET-1 mRNA表达,更大的ETA介导性反应,包括肾髓质血管收缩,以及更严重的肾损伤。这些差异在性腺切除后会减少,这表明是性激素(主要是睾丸激素)在起作用。相反,雌性动物相对来说通过ETB和ETA受体功能增强而能较少受高血压和肾损伤的伤害。此外,ETA受体可能对雌性动物排钠和减少肾损伤有有利的作用。在人体研究中,ET系统的遗传多态性与女性高血压和肾病的相关性更强。然而,关于ETA拮抗剂在高血压和肾病治疗中的疗效和不良事件性别差异的知识描述较少。对ET系统在肾脏中的性别差异作用提高认识,尤其是增强对受体亚型功能的认识,将能更好地治疗高血压和肾病。

To view the full version of this article please visit http://dx.doi.org/10.1111/j.1476-5381.2012.01922.x

查看全文请访问 http://dx.doi.org/10.1111/j.1476-5381.2012.01922.x

Early progress in epigenetic regulation of endothelin pathway genes

  1. Top of page
  2. Themed section: endothelin
  3. Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer
  4. The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth
  5. ET-1 actions in the kidney: evidence for sex differences
  6. Early progress in epigenetic regulation of endothelin pathway genes
  7. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour?
  8. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans
  9. Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold
  10. Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors
  11. Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model
  12. Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis
  13. Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem
  14. Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR2) is involved in vascular function
  15. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation
  16. NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease
  17. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2
  18. Pharmacological characterization of designer cathinones in vitro
  19. Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system
  20. The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10
  21. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

内皮素通路基因表观遗传调节的早期进展

AK Welch1, ME Jacobs1, CS Wingo2,3 and BD Cain1
1Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA, 2Department of Medicine, University of Florida, Gainesville, FL, USA, and 3North Florida/South Georgia VA Medical Center, Gainesville, FL, USA

控制基因转录是内皮素通路功能的主要调控决定因素。表观遗传机制在发育期间和出现生理刺激时会对组织特异性基因表达起作用。在有关内皮素通路表观遗传调节的有限证据中,大部分是针对EDN1EDNRB基因的。对全基因组数据库的检查表明,这两种基因都会受到组织蛋白修饰和DNA甲基化的影响。这种解释得到那些旨在检测表观遗传对这两种基因作用的相关研究的支持。对表观遗传因子改变内皮素信号的最清楚解释,是肿瘤发生期间的DNA甲基化相关EDNRB基因沉默。本综述总结了我们当前对内皮素通路基因表观遗传调节的理解。

To view the full version of this article please visit http://dx.doi.org/10.1111/j.1476-5381.2012.01826.x

查看全文请访问 http://dx.doi.org/10.1111/j.1476-5381.2012.01826.x

Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour?

  1. Top of page
  2. Themed section: endothelin
  3. Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer
  4. The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth
  5. ET-1 actions in the kidney: evidence for sex differences
  6. Early progress in epigenetic regulation of endothelin pathway genes
  7. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour?
  8. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans
  9. Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold
  10. Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors
  11. Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model
  12. Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis
  13. Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem
  14. Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR2) is involved in vascular function
  15. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation
  16. NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease
  17. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2
  18. Pharmacological characterization of designer cathinones in vitro
  19. Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system
  20. The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10
  21. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

小分子葡萄糖激酶活化剂:又一个抗糖尿病新治疗药失宠了吗?

Matthew G Rees1,2 and Anna L Gloyn1
1Oxford Centre for Diabetes Endocrinology & Metabolism, University of Oxford, Oxford, UK, and 2National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

葡萄糖激酶活化剂(GKAs)是最有希望成为下一代2型糖尿病(T2D)治疗药的药物之一,在T2D动物模型和短期人体试验中显示有降低血糖和HbA1c水平的疗效。人们早就已经认识到胰岛β细胞中的GCK激活有低血糖风险,而GKAs的肝脏作用通常被认为没有显著副作用。根据本期《英国药理学期刊》(British Journal of Pharmacology)中发表的De Ceuninck等人的报告,正常血糖和高血糖啮齿类动物模型被急性和慢性GKA处理后,肝脏中会出现显著的甘油三酸酯积聚。这表明,GKA介导的肝脏葡萄糖摄取激活和内源性葡萄糖生成抑制是要付出代价的;换句话说,就是会发展为肝脂肪变性。这就提出了有关GKAs安全性的重大问题,并强调,对这些分子正在进行的和未来的研究中,必须认真监测血浆和肝脏的脂质特征。

To view the full version of this article please visit http://dx.doi.org/10.1111/j.1476-5381.2012.02201.x

查看全文请访问 http://dx.doi.org/10.1111/j.1476-5381.2012.02201.x

Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans

  1. Top of page
  2. Themed section: endothelin
  3. Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer
  4. The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth
  5. ET-1 actions in the kidney: evidence for sex differences
  6. Early progress in epigenetic regulation of endothelin pathway genes
  7. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour?
  8. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans
  9. Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold
  10. Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors
  11. Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model
  12. Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis
  13. Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem
  14. Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR2) is involved in vascular function
  15. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation
  16. NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease
  17. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2
  18. Pharmacological characterization of designer cathinones in vitro
  19. Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system
  20. The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10
  21. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

小分子葡萄糖激酶激活剂能打破啮齿类动物的脂质平衡和诱导脂肪肝:对人体治疗性应用的警告

Frédéric De Ceuninck1, Catherine Kargar1, Catherine Ilic1, Audrey Caliez1, Jean-Olivier Rolin1, Thierry Umbdenstock2, Cédric Vinson3, Murielle Combettes1, Brant de Fanti1, Elizabeth Harley1, Marjorie Sadlo1, Anne-Laure Lefèvre1, Olivier Broux1, Michel Wierzbicki4, Jean-Marie Fourquez4, Françoise Perron-Sierra4, András Kotschy5 and Alain Ktorza1
1Division of Metabolic Diseases, Institut de Recherches Servier, Suresnes, France, 2DMPK Predevelopment, Technologie Servier, Orléans, France, 3Biopharmaceutical Coordination, Technologie Servier, Orléans, France, 4Division of Medicinal Chemistry, Institut de Recherches Servier, Suresnes, France, and 5Servier Research Institute of Medicinal Chemistry, Budapest, Hungary

背景和目的:小分子葡萄糖激活剂(GKAs)目前正被作为2型糖尿病(T2D)的治疗选择进行研究。因为葡萄糖激酶的肝脏过表达被认为与脂质特征变化相关,所以本研究的目的是评估与口服应用GKA相关的潜在生脂风险。

实验方法:9种GKA候选药有能力激活重组葡萄糖激酶,并刺激大鼠肝细胞中的糖原合成和大鼠INS-1E细胞中的胰岛素分泌。啮齿类动物口服给药后,通过血糖和HbA1c测定进行体内活性监测。通过测定肝脏和血浆甘油三酸酯和游离脂肪酸,以及血浆转氨酶和碱性磷酸酶,评估风险相关作用。

关键结果:GKAs虽然在高血糖症db/db小鼠长期应用后能有效降低急性条件下的血糖和HbA1c水平,但它是强劲的脂肪肝诱导剂。每天口服应用药理学剂量的GKAs,这种不良结局在四天后会很快出现,并且不是瞬时性的。GKA处理同样能升高糖尿病和血糖正常大鼠的肝脏甘油三酸酯水平,同时有一个代谢表现型模式,包括不同组合形式的血浆甘油三酸酯、游离脂肪酸、丙氨酸和天冬氨酸氨基转移酶、碱性磷酸酶水平升高。属于3种不同结构家族的GKAs能诱导db/db小鼠的脂肪肝,支持其有靶点介导的而不是化学类别介导的作用。

结论与启示:鉴于GKAs在一般人群和在T2D患者群中的脂肪肝疾病相关风险,这些研究发现未尝不是对人体应用GKAs提出的一个严重警告。

To view the full version of this article please visit http://dx.doi.org/10.1111/j.1476-5381.2012.02184.x

查看全文请访问 http://dx.doi.org/10.1111/j.1476-5381.2012.02184.x

Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold

  1. Top of page
  2. Themed section: endothelin
  3. Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer
  4. The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth
  5. ET-1 actions in the kidney: evidence for sex differences
  6. Early progress in epigenetic regulation of endothelin pathway genes
  7. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour?
  8. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans
  9. Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold
  10. Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors
  11. Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model
  12. Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis
  13. Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem
  14. Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR2) is involved in vascular function
  15. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation
  16. NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease
  17. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2
  18. Pharmacological characterization of designer cathinones in vitro
  19. Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system
  20. The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10
  21. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

3-iodothyronamine (T1AM)在小鼠中的药理学作用包括促进记忆获得及保护和降低疼痛阈

Maria Elena Manni1, Gaetano De Siena1, Alessandro Saba2, Maja Marchini2, Elisa Landucci1, Elisabetta Gerace1, Marina Zazzeri1, Claudia Musilli1, Domenico Pellegrini-Giampietro1, Rosanna Matucci1, Riccardo Zucchi2 and Laura Raimondi1
1Department of Pharmacology, University of Florence, Florence, Italy, and 2Department of Pathology, University of Pisa, Pisa, Italy

背景和目的:甲状腺激素的内源性衍生物——3-Iodothyronamine (T1AM)——被认为是一种快速的行为和代谢调节剂。为了确定脑中的甲状腺激素水平是否促成了这些作用,我们观察了中枢应用T1AM对小鼠学习和痛阈的作用。小鼠分别未经药物处理,或者以胺类氧化代谢的抑制剂氯吉灵(2.5 mg/kg;腹腔注射)进行处理。

实验方法:向雄性小鼠侧脑室内注射T1AM (0.13、0.4、1.32和4 μg/kg) 或赋形剂,30分钟后通过以下测试评估它们对记忆获得能力、痛阈和好奇心的作用:被动回避,热盆舔足行为潜伏期和洞板平台运动。利用葡萄糖折射计(glucorefractometer)测定血浆血糖。通过结合串联质谱(MS)的高效液相色谱法(HPLC)测定三碘甲状腺素(T3)、甲状腺素(T4)和T1AM。通过Western blot法评估不同脑区的ERK1/2激活和c-fos基因表达。

关键结果:T1AM能以剂量依赖方式提高学习能力,降低热刺激的痛阈,增强好奇心,升高血浆血糖水平,而不会改变T3和T4的脑浓度。T1AM对学习和疼痛的作用被氯吉灵完全消除或显著影响,这表明对某些代谢物的作用,或者显示了T1AM在快速脱敏靶点上的作用。T1AM能以低于影响行为的剂量激活不同脑区的ERK。

结论与启示:T1AM是一种新的记忆增强剂。这种特性可能对内分泌和神经退行性记忆障碍的治疗有重要意义。

To view the full version of this article please visit http://dx.doi.org/10.1111/j.1476-5381.2012.02137.x

查看全文请访问 http://dx.doi.org/10.1111/j.1476-5381.2012.02137.x

Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors

  1. Top of page
  2. Themed section: endothelin
  3. Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer
  4. The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth
  5. ET-1 actions in the kidney: evidence for sex differences
  6. Early progress in epigenetic regulation of endothelin pathway genes
  7. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour?
  8. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans
  9. Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold
  10. Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors
  11. Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model
  12. Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis
  13. Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem
  14. Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR2) is involved in vascular function
  15. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation
  16. NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease
  17. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2
  18. Pharmacological characterization of designer cathinones in vitro
  19. Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system
  20. The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10
  21. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

辛伐他汀能选择性抑制IRF3磷酸化和dsRNA激发的COPD供体支气管上皮细胞中的TSLP生成

Angelica Brandelius1, Irma Mahmutovic Persson1, Jenny Calvén1, Leif Bjermer2, Carl GA Persson3, Morgan Andersson2 and Lena Uller1
1Department of Experimental Medical Science, Lund University, Lund, Sweden, 2Skane University Hospital, Lund, Sweden, and 3Division of Clinical Chemistry and Pharmacology, Lund University, Lund, Sweden

背景和目的:他汀类治疗能使病毒感染诱导性慢性阻塞性肺病(COPD)Th2型支气管炎的恶化状况得到改善。启动Th2炎症的中心细胞因子——胸腺基质淋巴细胞生成素(TSLP)——过度生成于病毒和dsRNA刺激的COPD供体的支气管上皮细胞中。因此,TSLP可能与COPD恶化有因果关系。本研究检验了一个猜想:辛伐他汀能抑制dsRNA诱导的TSLP。

实验方法:通过支气管镜检查从COPD患者(n = 7)和吸烟对照(n = 8)供体获得上皮细胞,以病毒感染和危险信号代替物dsRNA (10 μg/mL) 进行培养和刺激。在有或没有应用甲羟戊酸(mevalonate;13–26 μg/mL)的条件下,以辛伐他汀 (0.2–5 μg/mL) 处理细胞,或在应用dsRNA前应用地塞米松(1 μg/mL)。确定细胞因子表达和生成及转录因子(IRF3和NF-κB)的激活。

关键结果:dsRNA诱导了TSLP、TNF-α、CXCL8和IFN-β。与对照组相比,dsRNA暴露的COPD细胞中产生了过量的TSLP。辛伐他汀以浓度依赖性方式抑制dsRNA诱导的TSLP,但地塞米松没有该作用。出乎意料的是,辛伐他汀的作用不依赖于甲羟戊酸,既没有影响dsRNA诱导的NF-κB激活,也没有减少TNF-α和CXCL8的生成。相反,辛伐他汀能抑制dsRNA诱导的IRF3磷酸化和IFN-β的产生。

结论与启示:辛伐他汀不依赖于甲羟戊酸和NF-κB这些此前公认的多效性他汀类抗炎机制,选择性抑制了COPD 上皮细胞中dsRNA诱导的IRF3激活与TSLP和IFN-β的生成。这些资料为抑制TSLP诱导性肺免疫病理学提供了全新的TSLP上皮生成知识,提出了药物发现的开发途径。

To view the full version of this article please visit http://dx.doi.org/10.1111/j.1476-5381.2012.02131.x

查看全文请访问 http://dx.doi.org/10.1111/j.1476-5381.2012.02131.x

Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model

  1. Top of page
  2. Themed section: endothelin
  3. Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer
  4. The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth
  5. ET-1 actions in the kidney: evidence for sex differences
  6. Early progress in epigenetic regulation of endothelin pathway genes
  7. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour?
  8. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans
  9. Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold
  10. Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors
  11. Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model
  12. Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis
  13. Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem
  14. Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR2) is involved in vascular function
  15. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation
  16. NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease
  17. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2
  18. Pharmacological characterization of designer cathinones in vitro
  19. Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system
  20. The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10
  21. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

羟考酮和吗啡对骨癌痛模型疼痛相关脑区中μ-阿片受体的分化激活

Atsushi Nakamura1,2, Minoru Hasegawa1, Kazuhisa Minami1, Tomoe Kanbara1,2, Takako Tomii1, Atsushi Nishiyori1, Minoru Narita3, Tsutomu Suzuki2 and Akira Kato1
1Pain & Neurology, Discovery Research Laboratories, Shionogi Co., Ltd., Toyonaka, Osaka, Japan, 2Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa-ku, Tokyo, Japan, and 3Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa-ku, Tokyo, Japan

背景和目的:骨癌痛是长期存在的,常常不容易用阿片类来控制。然而最近有研究表明多种阿片类在慢性骨癌痛中有明显的镇痛特性。

实验方法:为清楚阐述这些显著镇痛特性的机制,我们利用一个小鼠股骨癌(FBC)模型观察了μ-阿片受体的功能变化。

关键结果:在FBC模型中,中脑导水管周围灰质(PAG)、中脑导水管周围灰质腹侧部(ePAG)、丘脑背内侧核(mTH)、丘脑腹侧和脊髓中[3H]-DAMGO结合的Bmax值被减少15–45%。羟考酮(10–8–10–5 M)和吗啡(10–8–10–5 M)能激活[35S]-GTPγS结合,但是在FBC模型中,这种激活作用在PAG、vPAG、mTH和脊髓内被显著减轻。有趣的是,在PAG、vPAG和mTH中(但不是在脊髓中),羟考酮诱导[35S]-GTPγS结合的减少与吗啡相比显得非常有限。此外,侧脑室(i.c.v.)应用剂量为每只小鼠0.02–1.0 μg的羟考酮明显地抑制了FBC模型小鼠的疼痛相关行为,例如守卫行为、肢体应用障碍和异常性疼痛样行为,但i.c.v.应用的吗啡(每只小鼠0.05–2.0 μg)对肢体应用障碍和异常性疼痛样行为只有部分或极少的镇痛作用。

结论与启示:这些结果显示,在骨癌的多个疼痛相关区,μ-阿片受体的功能可以激动剂依赖性方式被减弱,这表明,μ-阿片受体的修饰是羟考酮和吗啡显著镇痛作用的原因。

To view the full version of this article please visit http://dx.doi.org/10.1111/j.1476-5381.2012.02139.x

查看全文请访问 http://dx.doi.org/10.1111/j.1476-5381.2012.02139.x

Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis

  1. Top of page
  2. Themed section: endothelin
  3. Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer
  4. The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth
  5. ET-1 actions in the kidney: evidence for sex differences
  6. Early progress in epigenetic regulation of endothelin pathway genes
  7. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour?
  8. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans
  9. Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold
  10. Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors
  11. Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model
  12. Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis
  13. Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem
  14. Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR2) is involved in vascular function
  15. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation
  16. NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease
  17. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2
  18. Pharmacological characterization of designer cathinones in vitro
  19. Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system
  20. The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10
  21. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

激肽B1受体缺陷小鼠DSS诱导性结肠炎通过代偿性激肽B2受体上调的恶化:紧密连接和肠道稳态的作用

R Marcon1, RF Claudino1, RC Dutra1,3, AF Bento1, EC Schmidt2, ZL Bouzon2, R Sordi1, RLT Morais4, JB Pesquero4 and JB Calixto1
1Departamento de Farmacologia, 2Departamento de Biologia Celular, Embriologia e Genética, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil, 3Campus Araranguá, Universidade Federal de Santa Catarina, Araranguá, Santa Catarina, Brazil, and 4Departamento de Biofísica, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil

背景和目的:激肽是组织损伤包括炎症性肠病导致损伤时释放的促炎症性肽类。我们在本文中评估了激肽B1受体缺失在右旋糖苷钠盐(DSS)诱导性小鼠结肠炎发展恶化中发挥的作用及其潜在机制。

实验方法:用B1和B2受体拮抗剂和B1受体敲除小鼠(B1–/–)评估B1和B2受体信号在DSS结肠炎中的参与作用。评估野生型(WT)和B1–/–小鼠结肠中的B1受体、B2受体、紧密连接蛋白occludin和claudin-4表达、细胞因子水平和细胞通透性。

关键结果:与WT小鼠相比,B1–/–小鼠的DSS诱导性结肠炎显著恶化。与DSS处理的WT小鼠相比,DSS处理B1–/–小鼠的IL-1β、IFN-γ、角化细胞源性趋化因子和巨噬细胞炎症蛋白-2水平被显著提高。选择性B1受体拮抗剂DALBK或SSR240612的应用对DSS诱导性结肠炎没有作用。值得注意的是,B1–/–小鼠应用DSS后,其结肠组织中的B2受体mRNA表达被显著上调。此外,以选择性B2受体拮抗剂处理后,能够预防B1–/–小鼠应用DSS后的结肠炎恶化。B1–/–小鼠接受水或者DSS给药后,其occludin基因表达下降,该作用可被B2受体拮抗剂部分预防。

结论与启示:B1受体缺失可使DSS诱导小鼠结肠炎的严重性显著增加。B1–/–小鼠的易感性升高可能与B2受体的代偿性过表达相关,反过来,这又能调节紧密连接的表达。

To view the full version of this article please visit http://dx.doi.org/10.1111/j.1476-5381.2012.02136.x

查看全文请访问 http://dx.doi.org/10.1111/j.1476-5381.2012.02136.x

Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem

  1. Top of page
  2. Themed section: endothelin
  3. Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer
  4. The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth
  5. ET-1 actions in the kidney: evidence for sex differences
  6. Early progress in epigenetic regulation of endothelin pathway genes
  7. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour?
  8. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans
  9. Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold
  10. Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors
  11. Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model
  12. Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis
  13. Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem
  14. Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR2) is involved in vascular function
  15. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation
  16. NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease
  17. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2
  18. Pharmacological characterization of designer cathinones in vitro
  19. Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system
  20. The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10
  21. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

外周应用前动力蛋白2能通过脑干强效性降低小鼠的食物摄取量和体重

KEL Beale1, JV Gardiner1, GA Bewick1, K Hostomska1, NA Patel1, SS Hussain1, CN Jayasena1, FJP Ebling2, PH Jethwa2, HM Prosser3, R Lattanzi4, L Negri4, MA Ghatei1, SR Bloom1 and WS Dhillo1
1Section of Investigative Medicine, Imperial College London, London, UK, 2School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK, 3The Wellcome Trust Sanger Institute, Cambridge, UK, and 4Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

背景和目的:最近有研究表明前动力蛋白2(Prokineticin 2; PK2)能急性降低啮齿类动物的食物摄取量。本研究旨在确定介导外周应用PK2的食欲抑制作用的CNS位点和受体及其对葡萄糖和能量平衡的慢性作用。

实验方法:我们利用c-Fos样免疫反应(CFL-IR)研究了腹腔注射PK2后的神经元激活。在前动力蛋白受体1(PKR1)或前动力蛋白受体2(PKR2)靶向删除的小鼠中和应用PKR1拮抗剂PC1之后的野生型小鼠中,观察PK2对小鼠的食欲抑制作用。了解腹腔注射PK2对葡萄糖平衡的作用。最后研究食物诱导对肥胖(DIO)大鼠长期应用PK2对葡萄糖和能量平衡的作用。

关键结果:腹腔注射PK2后能显著升高脑干迷走神经背核中的CFL-IR。PK2的食欲抑制作用维持于PKR2缺陷小鼠中,但在PKR1缺陷小鼠和PC1预处理野生型小鼠中被消除。慢性应用PK2的DIO小鼠的葡萄糖水平没有变化,但与对照组相比,其食物摄取量和体重显著下降。

结论与启示:综上所述,我们的研究资料表明,外周应用PK2的食欲抑制作用是经脑干介导的,该作用必须要有PKR1信号但不需要PKR2信号。在人肥胖小鼠模型中慢性应用的PK2能减少食物摄取和减轻体重,这表明PKR1选择性激动剂有作为肥胖治疗新药的潜力。

To view the full version of this article please visit http://dx.doi.org/10.1111/j.1476-5381.2012.02191.x

查看全文请访问 http://dx.doi.org/10.1111/j.1476-5381.2012.02191.x

Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR2) is involved in vascular function

  1. Top of page
  2. Themed section: endothelin
  3. Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer
  4. The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth
  5. ET-1 actions in the kidney: evidence for sex differences
  6. Early progress in epigenetic regulation of endothelin pathway genes
  7. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour?
  8. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans
  9. Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold
  10. Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors
  11. Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model
  12. Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis
  13. Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem
  14. Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR2) is involved in vascular function
  15. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation
  16. NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease
  17. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2
  18. Pharmacological characterization of designer cathinones in vitro
  19. Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system
  20. The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10
  21. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

Toll样受体4(TLR4)与蛋白酶激活受体2(PAR2)之间的串扰与心脏功能有关

M Bucci1, V Vellecco1, L Harrington2, V Brancaleone1,5, F Roviezzo1, G Mattace Raso1, A Ianaro1, G Lungarella3, R De Palma4, R Meli1 and G Cirino1
1Department of Experimental Pharmacology, Faculty of Pharmacy, University of Naples ‘Federico II’, Napoli, Italy, 2Cardiothoracic Pharmacology, Imperial College, London, UK, 3Department of Physiopathology and Experimental Medicine, University of Siena, Siena, Italy, 4Dipartimento di Internistica Clinica e Sperimentale, Seconda Università di Napoli, Napoli, Italy, and 5Dipartimento di Scienze, Università degli Studi della Basilicata, Potenza, Italy

背景和目的:蛋白酶激活受体(PARs)和toll样受体(TLRs)与先天性免疫反应有关。本研究的目的是利用体内和体外模型评估血管中的PAR2与TLR4在生理学条件下可能存在的串扰,及其在激活TLR4后如何发生变化。

实验方法:体外研究中,从未经药物处理的大鼠和内毒素血症大鼠中取得胸主动脉。体内研究中,监测麻醉大鼠的动脉血压。将LPS用作TLR4激动剂,而以PAR2激活肽(AP)为PAR2激动剂。利用从TLR4−/−小鼠获得的主动脉来鉴定PAR2反应。

关键结果:内毒素血症大鼠的PAR2表达被增强,但是TLR4表达无该反应。在经LPS处理的大鼠主动脉环中,PAR2AP诱导的血管舒张被增强。TLR4抑制剂——姜黄素和白藜芦醇——能降低未经药物处理的大鼠和内毒素血症大鼠的PAR2AP诱导性血管舒张和PAR2AP诱导性低血压。最后,与野生型小鼠相比,TLR4−/−小鼠主动脉环中的PAR2表达被减少,PAR2AP诱导的血管扩张受损;白藜芦醇和姜黄素都没有效果。

结论与启示:PAR2与TLR4之间的串扰能促进血管稳态。

To view the full version of this article please visit http://dx.doi.org/10.1111/j.1476-5381.2012.02205.x

查看全文请访问 http://dx.doi.org/10.1111/j.1476-5381.2012.02205.x

Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation

  1. Top of page
  2. Themed section: endothelin
  3. Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer
  4. The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth
  5. ET-1 actions in the kidney: evidence for sex differences
  6. Early progress in epigenetic regulation of endothelin pathway genes
  7. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour?
  8. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans
  9. Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold
  10. Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors
  11. Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model
  12. Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis
  13. Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem
  14. Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR2) is involved in vascular function
  15. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation
  16. NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease
  17. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2
  18. Pharmacological characterization of designer cathinones in vitro
  19. Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system
  20. The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10
  21. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

黄芩素能减轻γ-射线辐射诱导的海马神经发生受损和神经认知功能缺陷

Shin Bi Oh1, Hee Ra Park1, Young Jung Jang1, Seon Young Choi1, Tae Gen Son2 and Jaewon Lee1
1Department of Pharmacy, College of Pharmacy, and Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Geumjeong-gu, Busan, Korea, and 2Department of Experimental Radiation, Research Center, Dongnam Institute of Radiological and Medical Science, Jangan-eup, Gijang-gun, Busan, Korea

背景和目的:全脑照射(WBI)治疗可能使脑瘤患者出现学习能力和记忆障碍。虽然认知缺陷的病理性级联还不为人知,但可能涉及海马中的神经形成减少。黄芩素(Baicalein)是一种来源于黄芩(Scutellaria baicalensis Georgi)根的黄酮类,研究显示其有抗氧化作用。我们在本文中研究了黄芩对辐射诱导性海马神经形成和认知功能障碍的保护作用。

实验方法:在海马神经形成期间,评估黄芩在C17.2神经祖细胞和6周龄雄性C57BL/6小鼠中的防辐射作用。小鼠单次应用5 Gy的WBI。评估海马神经形成、氧化应激和BDNF-pCREB信号的变化。用莫里斯水迷宫实验(Morris water maze)和被动回避实验评估学习能力和记忆功能。

关键结果:黄芩能使神经祖细胞免于辐射诱导的坏死性细胞死亡。经黄芩预处理后,能通过调控氧化应激和增强BDNF-pCREB信号减轻辐射诱导的海马神经形成障碍。此外,黄芩能预防WBI之后的空间学习能力和记忆保持缺陷。

结论与启示:本研究发现表明,黄芩可以被视为一种能预防WBI诱导的神经形成障碍和预防其神经认知功能影响的潜在治疗药。

To view the full version of this article please visit http://dx.doi.org/10.1111/j.1476-5381.2012.02142.x

查看全文请访问 http://dx.doi.org/10.1111/j.1476-5381.2012.02142.x

NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease

  1. Top of page
  2. Themed section: endothelin
  3. Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer
  4. The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth
  5. ET-1 actions in the kidney: evidence for sex differences
  6. Early progress in epigenetic regulation of endothelin pathway genes
  7. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour?
  8. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans
  9. Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold
  10. Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors
  11. Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model
  12. Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis
  13. Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem
  14. Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR2) is involved in vascular function
  15. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation
  16. NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease
  17. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2
  18. Pharmacological characterization of designer cathinones in vitro
  19. Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system
  20. The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10
  21. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

新型KCa3.1通道抑制剂——NS6180——在大鼠炎性肠病模型中能阻止T细胞激活和炎症

D Strøbæk1, DT Brown1, DP Jenkins2, Y-J Chen2, N Coleman2, Y Ando3, P Chiu4, S Jørgensen1, J Demnitz1, H Wulff2 and P Christophersen1
1NeuroSearch A/S, Ballerup, Denmark, 2Department of Pharmacology University of California, Davis, CA, USA, 3Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, USA, and 4Ricerca Biosciences LLC, Bothell, WA, USA

背景和目的:KCa3.1通道是一个治疗免疫疾病的潜在靶点。我们从一个KCa3.1抑制剂新化学类别中确定一个化合物,评估了其对免疫疾病的体外和体内抑制。

实验方法:鉴定苯并噻嗪NS6180(4-[[3-(三氟甲基)苯基]甲基]-2H-1,4-苯并噻嗪-3(4H)-酮)的作用强度和对KCa3.1通道的分子作用位点、对其他靶点的选择性、对T细胞激活的作用,和在2,4-二硝基苯磺酸诱导性结肠炎(大鼠炎症性肠病模型)中的药代动力学和炎症控制作用。

关键结果:NS6180能通过象TRAM-34一样给三芳基甲烷赋予敏感性的氨基酸残基T250和V275抑制克隆人KCa3.1通道(IC50 = 9 nM)。NS6180能抑制人、小鼠和大鼠红细胞中内源性表达的KCa3.1通道,有着相似的抑制强度(15–20 nM)。NS6180能以亚微摩尔浓度抑制大鼠和小鼠的脾细胞增殖,强效抑制IL-2和FN-γ的生成,但对IL-4和TNF-α的作用较小,而对IL-17生成完全没有作用。抗体染色显示了诱导结肠炎后健康结肠中的KCa3.1通道和与浸润免疫细胞相关的强烈上调。虽然血浆暴露水平很低,但是NS6180(3和10 mg/kg,口服)能抑制结肠炎症和促进体重增加,效果与标准的IBD治疗药柳氮磺胺吡啶(sulfasalazine;300 mg/kg,每日一次给药)一样。

结论与启示:NS6180代表了一类能抑制实验性结肠炎的新型KCa3.1通道抑制剂,这表明KCa3.1通道是药理学控制肠炎的靶点。

To view the full version of this article please visit http://dx.doi.org/10.1111/j.1476-5381.2012.02143.x

查看全文请访问 http://dx.doi.org/10.1111/j.1476-5381.2012.02143.x

An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2

  1. Top of page
  2. Themed section: endothelin
  3. Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer
  4. The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth
  5. ET-1 actions in the kidney: evidence for sex differences
  6. Early progress in epigenetic regulation of endothelin pathway genes
  7. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour?
  8. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans
  9. Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold
  10. Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors
  11. Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model
  12. Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis
  13. Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem
  14. Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR2) is involved in vascular function
  15. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation
  16. NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease
  17. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2
  18. Pharmacological characterization of designer cathinones in vitro
  19. Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system
  20. The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10
  21. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

一个确定抗体-药物偶联物靶点正常组织表达的综合方法:TENB2的病例研究

C Andrew Boswell, Eduardo E Mundo, Ron Firestein, Crystal Zhang, Weiguang Mao, Herman Gill, Cynthia Young, Nina Ljumanovic, Shannon Stainton, Sheila Ulufatu, Aimee Fourie, Katherine R Kozak, Reina Fuji, Paul Polakis, Leslie A Khawli and Kedan Lin
Genentech Research and Early Development, South San Francisco, CA, USA

背景和目的:抗体-药物偶联物(ADCs)的成功取决于正常和病理组织间不同表达转化的治疗窗。确定和显示正常组织中的靶向表达有可能揭示药代动力学鉴定中观察到的靶点介导清除的原因。TENB2是一个与分化不良和雄激素非依赖性肿瘤类型的进程相关的前列腺癌靶点,TENB2特异性ADCs是候选治疗药。本研究的目的是确定正常组织中TENB2抗原表达的位置,进而阐述靶点介导性清除的潜在原因。

实验方法:利用配体标记的抗TENB2 ADC对小鼠进行药代动力学、组织分布和质量平衡等一系列研究,配合无创性单光子发射计算机断层扫描即X射线计算机断层成像和免疫组化分析进行研究。

关键结果:肠道被确定至少在一定程度上促成了抗TENB2抗体及其药物偶联物在啮齿类动物中的快速靶点介导性清除。作为一个概念验证,我们也利用LuCaP 77移植小鼠模型在一个体内肿瘤环境中证明了ADC的选择性处置。尽管出现了抗原下降,但是我们观察到了很高的肿瘤吸收率,抗原特异性可从抗原阻断证实。

结论与启示:我们的发现为靶点介导抗TENB2抗体和相应药物偶联物的清除提供了解剖学定位和生物学解释。进一步研究将有利于解决正常和病理组织中的抗原表达对ADC处置的相对作用问题。

To view the full version of this article please visit http://dx.doi.org/10.1111/j.1476-5381.2012.02138.x

查看全文请访问 http://dx.doi.org/10.1111/j.1476-5381.2012.02138.x

Pharmacological characterization of designer cathinones in vitro

  1. Top of page
  2. Themed section: endothelin
  3. Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer
  4. The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth
  5. ET-1 actions in the kidney: evidence for sex differences
  6. Early progress in epigenetic regulation of endothelin pathway genes
  7. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour?
  8. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans
  9. Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold
  10. Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors
  11. Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model
  12. Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis
  13. Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem
  14. Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR2) is involved in vascular function
  15. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation
  16. NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease
  17. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2
  18. Pharmacological characterization of designer cathinones in vitro
  19. Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system
  20. The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10
  21. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

设计药cathinones的体外药理学鉴定

LD Simmler1, TA Buser1, M Donzelli1, Y Schramm2, L-H Dieu3, J Huwyler3, S Chaboz4, MC Hoener4 and ME Liechti1
1Division of Clinical Pharmacology and Toxicology, Departments of Biomedicine and Internal Medicine, University Hospital and University of Basel, Basel, Switzerland, 2Department of Chemistry, University of Basel, Basel, Switzerland, 3Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland, and 4Pharmaceuticals Division, Neuroscience Research, F.Hoffmann-La Roche Ltd, Basel, Switzerland

背景和目的:设计药β-酮基安非他明(例如cathinones、“浴盐”和“研究化学品”)已经成为非常流行的娱乐性药物,但是它们的药理学特点尚未得到充分鉴定。

实验方法:确定cathinones对多巴胺(DA)、去甲肾上腺素(NA)和5-羟色胺(5-HT)向转运体转染HEK 293细胞中转运、单胺预载细胞的DA和5-HT外流和单胺受体结合亲和性的抑制强度。

关键结果:Mephedrone、methylone、ethylone、butylone和naphyrone有非选择性单胺摄取抑制剂的作用,类似于可卡因。Mephedrone、methylone、ethylone和butylone也能诱导5-HT的释放,与3,4-亚甲基二氧基甲基苯丙胺(MDMA,俗称“摇头丸”)和其他“放心药”相似。Cathinone、methcathinone和flephedrone 与安非他明和甲基安非他明一样,也有优先性DA和NA转运体抑制剂的作用,但与安非他明不同的是它不能诱导单胺的释放。非β-酮安非他明是微量胺相关受体1配体,但cathinones却不是。在体外模型中,所有cathinones都显示出很高的血脑屏障渗透性;mephedrone和MDPV也展示了特别高的渗透性。

结论与启示:Cathinones的药理学有很大差异,基于这些差异,它们被建议归为三组。所有Cathinones对DA转运体的主要作用都很可能与极高的成瘾风险相关。

To view the full version of this article please visit http://dx.doi.org/10.1111/j.1476-5381.2012.02145.x

查看全文请访问 http://dx.doi.org/10.1111/j.1476-5381.2012.02145.x

Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system

  1. Top of page
  2. Themed section: endothelin
  3. Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer
  4. The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth
  5. ET-1 actions in the kidney: evidence for sex differences
  6. Early progress in epigenetic regulation of endothelin pathway genes
  7. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour?
  8. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans
  9. Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold
  10. Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors
  11. Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model
  12. Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis
  13. Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem
  14. Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR2) is involved in vascular function
  15. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation
  16. NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease
  17. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2
  18. Pharmacological characterization of designer cathinones in vitro
  19. Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system
  20. The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10
  21. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

人肺成纤维细胞中的促纤维化过程受自分泌/旁分泌内皮能系统的驱动

AS Ahmedat1, M Warnken1, WK Seemann2, K Mohr2, E Kostenis3, UR Juergens4 and K Racké1
1Institute of Pharmacology & Toxicology, University of Bonn, Bonn, Germany, 2Pharmacology & Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany, 3Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany, and 4Department Pulmonary Diseases, Med. Clinic and Policlinic II, University Bonn, Bonn, Germany

背景和目的:由于内皮素(ET)有作为促纤维化介质的作用,因此本文在人肺成纤维细胞中研究了ET亚型的表达和释放、它们的受体和潜在促纤维化ET作用。

实验方法:培养MRC-5和原代人肺成纤维细胞(phLFb)。分别通过qPCR和ELISA法确定前内皮素原(prepro-ET)亚型的表达和ET-1的释放。通过对实时动态质量再分布(DMR)的测定分析ET受体的功能。通过[3H]-胸腺嘧啶核苷掺入确定细胞增殖,以[3H]-脯氨酸掺入确定胶原合成。通过Western blot确定Phospho-p42/44 MAP激酶。

关键结果:ET-1是人肺成纤维细胞(hLF)中的主要ET,TGF-β能引起更具选择性和持续性的ET-1上调,导致细胞内ET-1积聚增加。hLFb可表达编码ET-A和ET-B受体的mRNA。在蛋白水平确定有两种受体的表达。ET-1诱导了显著的DMR信号,该作用有ET-A和ET-B受体的参与。ET-1对hLFb增殖和胶原合成的刺激作用完全是经ET-A受体介导的。ET-1同样也经ET-A受体诱导了ERK MAPK的快速激活,这是ET-1诱导胶原合成中的关键性细胞信号。ET-1诱导激活的ERK和胶原合成与毒蕈碱受体激动剂的相应作用不同,它在很大程度上对百日咳毒素是不敏感的。

结论与启示:hLFb具有建立功能性自分泌/旁分泌内皮能(endothelinergic)系统所必须的所有元素;自分泌/旁分泌内皮能系统似乎能驱动促纤维化的气道和肺重构过程,对于这些作用,似乎只有ET-A(而不是ET-B)受体有重要影响。

To view the full version of this article please visit http://dx.doi.org/10.1111/j.1476-5381.2012.02190.x

查看全文请访问 http://dx.doi.org/10.1111/j.1476-5381.2012.02190.x

The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10

  1. Top of page
  2. Themed section: endothelin
  3. Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer
  4. The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth
  5. ET-1 actions in the kidney: evidence for sex differences
  6. Early progress in epigenetic regulation of endothelin pathway genes
  7. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour?
  8. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans
  9. Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold
  10. Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors
  11. Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model
  12. Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis
  13. Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem
  14. Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR2) is involved in vascular function
  15. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation
  16. NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease
  17. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2
  18. Pharmacological characterization of designer cathinones in vitro
  19. Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system
  20. The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10
  21. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

C5a受体拮抗剂PMX205能改善实验诱导的IL-4和IL-10水平升高相关性结肠炎

U Jain1, TM Woodruff2 and AW Stadnyk1,3
1Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada, 2School of Biomedical Sciences, University of Queensland, Brisbane, Qld, Australia, and 3Department of Pediatrics, Dalhousie University, Halifax, NS, Canada

背景和目的:以抗补体疗法治疗炎性肠病(IBDs)仍未获得进展,但是越来越多的证据已经表明,阻断C5a能防止啮齿类动物的诱导性结肠炎。本研究的目的是在一个小鼠先天性结肠炎右旋葡聚糖硫酸钠(DSS)模型中,通过检验一种强效非竞争性的有口服活性的C5a受体(CD88)拮抗剂——PMX205——的疗效、作用机制和特异性,进一步巩固该证据。

实验方法:将DSS添加到小鼠的饮用水中,在预防性和治疗性给药方案中,给小鼠口服应用100或200 μg/天的PMX205。检查临床疾病、结肠病史和炎症介质的局部生成,评估PMX205对疾病的影响。

关键结果:在两种给药方案中,PMX205都能显著预防DSS诱导的结肠炎症,与结肠段中较低水平的促炎症性细胞因子生成和硝基酪氨酸染色相关。

此外,抗炎症细胞因子IL-4和IL-10的水平已被升高。PMX205对C5a水平没有显著作用。PMX205的有益作用可见于两个对DSS炎症有不同敏感性的小鼠品系,但在CD88缺陷小鼠中不活跃。

结论与启示:以PMX205药理学抑制C5a活性能有效预防DSS诱导性结肠炎,进一步以证据表明靶向IBD患者的CD88可能是一个有价值的治疗选择。

To view the full version of this article please visit http://dx.doi.org/10.1111/j.1476-5381.2012.02183.x

查看全文请访问 http://dx.doi.org/10.1111/j.1476-5381.2012.02183.x

Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

  1. Top of page
  2. Themed section: endothelin
  3. Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer
  4. The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth
  5. ET-1 actions in the kidney: evidence for sex differences
  6. Early progress in epigenetic regulation of endothelin pathway genes
  7. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour?
  8. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans
  9. Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold
  10. Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors
  11. Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model
  12. Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis
  13. Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem
  14. Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR2) is involved in vascular function
  15. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation
  16. NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease
  17. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2
  18. Pharmacological characterization of designer cathinones in vitro
  19. Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system
  20. The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10
  21. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

NMDA受体功能异常可使实验性自身免疫性脑脊髓炎恶化

G Grasselli1,8, S Rossi1,2, A Musella1, A Gentile1, S Loizzo3, L Muzio5, C Di Sanza1, F Errico6, G Musumeci1, N Haji1, D Fresegna1, H Sepman1, V De Chiara1,2, R Furlan5, G Martino5, A Usiello6,7,4, G Mandolesi1 and D Centonze1,2
1Fondazione Santa Lucia/Centro Europeo per la Ricerca sul Cervello (CERC), 2Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, 3Department of Therapeutic Research and Medicines Evaluation, 00161 Istituto Superiore di Sanità, 4European Brain Research Institute (EBRI), Rome, 5Neuroimmunology Unit-DIBIT, INspE, Division of Neuroscience, San Raffaele Scientific Institute, Milan, 6Behavioural Neuroscience Laboratory, CEINGE – Biotecnologie Avanzate, Naples, 7Dipartimento di Scienze Ambientali, Seconda Università di Napoli, Caserta, Italy, and 8Department of Neurobiology, University of Chicago, Chicago, IL, USA

背景和目的:谷氨酸盐传递可因多发性硬化症(MS)和实验性自身免疫性脑脊髓炎(EAE)这个MS的动物模型而失调。EAE的特点之一是与AMPA受体上调相关的谷氨酸盐传递升高。然而,有关NMDA在EAE诱导突触修饰中的作用所知甚少。

实验方法:通过神经生理学、形态学、Western blot、代谢和临床评分等方法,评估NMDA受体对谷氨酸盐传递和EAE小鼠疾病严重性的影响。

关键结果:在本研究的EAE小鼠中,出现了NMDA受体依赖性谷氨酸盐释放增加,与星形胶质细胞的显著激活相关。EAE期间的突触前NMDA受体过度活跃,以电压门控钠通道依赖机制提高了突触谷氨酸盐释放。通过NAD(P)H自体荧光分析,我们也发现,EAE有谷氨酸盐和NMDA受体依赖性线粒体活性失调,能导致MS和EAE的神经退行性损伤。此外,NMDA受体的体内药理学阻断能改善EAE小鼠的突触传递障碍和临床病程,但是通过基因强化NMDA受体信号诱导的小鼠EAE有相反的作用。

结论与启示:我们的资料既显示了NMDA受体的致敏作用,又显示了它们在EAE病程中的参与作用,这表明,药理学破坏NMDA受体信号将有可能是MS神经保护策略的一部分。

To view the full version of this article please visit http://dx.doi.org/10.1111/j.1476-5381.2012.02178.x

查看全文请访问 http://dx.doi.org/10.1111/j.1476-5381.2012.02178.x