Modulation of neurotransmitter systems by dehydroepiandrosterone and dehydroepiandrosterone sulfate: mechanism of action and relevance to psychiatric disorders

Dehydroepiandrosterone (DHEA) is synthesized in the brain and several studies have shown that this steroid is a modulator of synaptic transmission. The effect of DHEA, and its sulfate ester DHEAS, on glutamate and GABA neurotransmission has been extensively studied but some effects on other neurotransmitter systems, such as dopamine, serotonin and nitric oxide, have also been reported. This review summarizes studies showing the effect of DHEA and DHEAS on neurotransmitter systems at different levels (metabolism, release, reuptake, receptor activation), as well as the activation of voltage-gated ion channels and calcium homeostasis, showing the variety of effects that these steroids exert on those systems, allowing the discussion of its mechanisms of action and its relevance to psychiatric disorders.     

Calciphylaxis: calcific uremic arteriolopathy and the emerging role of sodium thiosulfate

Calciphylaxis–calcific uremic arteriolopathy, is a serious disorder of arteriolar calcification of the arteriole media and is associated with endovascular fibrosis and thrombosis in subcutaneous adipose tissue. It frequently results in severe ischemia, intense pain, and tissue necrosis with nonhealing skin ulcerations. It usually occurs in chronic kidney disease and especially in patients requiring renal replacement therapy. It is associated with a very high mortality rate, and the number of reports and reviews seemed to have increased over the past 5 years. Advances in therapy and salvaging patients from this high mortality risk have recently been reported with the use of sodium thiosulfate. The new application for this old drug used to treat cyanide poisoning and recently preventing neurotoxic effects resulting in hearing loss in those patients with head and neck cancer receiving cisplatin and carboplatin therapy are discussed. Recently, multiple case reports have demonstrated that sodium thiosulfate therapy has resulted in rapid pain relief, healing of skin ulcerations, and prevention of high mortality risk. This emerging treatment and its success are relatively unknown to many physicians. The purpose of this report is to share with others the emerging role of sodium thiosulfate and its new application as a treatment option to be used in combination with other treatment modalities for calciphylaxis–calcific uremic arteriolopathy. Indeed, as with any new treatment this emerging therapy should be studied in greater detail, but this old drug seems to have a new life in the hands of treating physicians.     

Nitric oxide-dependent vasodilatation by ethanolic extract of Hancornia speciosa via phosphatidyl-inositol 3-kinase

The vasodilator effect of the ethanolic extract of leaves from Hancornia speciosa Gomes (HSE) was studied in rat aortic rings. HSE produced a concentration-dependent vasodilatation (pIC(50)=5.6+/-0.1), which was completely abolished in endothelium-denuded vessels. The endothelium-dependent vasodilatation induced by HSE was abolished by l-NAME (100 microM), a nitric oxide (NO) synthase inhibitor, but not atropine (1 microM; pIC(50)=5.6+/-0.2), a muscarinic receptor antagonist, nor indomethacin (10 microM; pIC(50)=5.4+/-0.2), a cyclooxygenase inhibitor. The concentration-response curve of HSE was significantly shifted to the left by superoxide dismutase (SOD; 300U/mL). In addition, while SOD displaced the 3-morpholino-sidnonimine (SIN-1; P<0.05) concentration-effect curve to the left, HSE (50 microg/mL) had no effect. Finally, wortmannin (0.3 microM), an inhibitor of phosphatidyl-inositol 3-kinase (PI3K), dramatically reduced the vasodilator effect of HSE. Together, these findings lead us to conclude that HSE induces a NO- and endothelium-dependent vasodilatation in rat aortic preparations, likely by a mechanism dependent on the activation of PI3K.     

IMMUNOHISTOCHEMICAL LOCALIZATION OF ENDOTHELIAL ISOFORM (eNOS) IN HUMAN CEREBRAL ARTERIES AND THE AORTA

The common carotid, vertebral, posterior cerebral arteries, and the aorta were studied in the human in terms of its eNOS expression. In around 10 weeks of gestation, the developing intima began to express notable eNOS. In the adult, the positive eNOS sites were in the endothelial cells and the tunica media where the smooth muscles were. In the vessels with athrosclerotic changes, eNOS was down regulated in the endothelial layer and most of the tunica media but was significantly upregulated in the tunica media around the lesion. The protein changes are related to the onset of the athrosclerotic diseases.     

SIRT1/eNOS/NO通路在人参皂苷Rb1抗内皮细胞复制性衰老中的作用

目的:观察人参皂苷Rb1延缓人脐静脉内皮细胞(HUVECs)复制性衰老的作用,并探讨SIRT1/e NOS/NO通路在其中的作用机制。方法:建立原代HUVECs复制性衰老模型,根据细胞形态的变化、衰老相关β-半乳糖苷酶(SA-β-Gal)染色阳性率和纤溶酶原激活物抑制剂1(PAI-1)的表达水平评估HUVECs衰老情况;采用real-time PCR方法和Western blot法检测沉默SIRT1前后衰老细胞中e NOS和PAI-1的mRNA和蛋白表达,并检测细胞上清NO的含量。结果:累积细胞群体倍增水平(CPDL)为16的HUVECs可作为复制性衰老模型; 80μmol/L人参皂苷Rb1处理后衰老细胞内SIRT1和eNOS的mRNA及蛋白表达水平增加,NO含量增加(P 0. 05),而PAI-1的mRNA和蛋白表达水平下降(P 0. 05);沉默SIRT1后,衰老细胞内e NOS的mRNA及蛋白表达减少,PAI-1的mRNA及蛋白表达增加,NO含量减少(P 0. 05);与SIRT1沉默组比较,在沉默SIRT1基础上加用人参皂苷Rb1后,e NOS和PAI-1表达水平及NO的含量未见明显变化。结论:人参皂苷Rb1可通过调控SIRT1/e NOS/NO通路延缓HUVECs复制性衰老。     

人参皂苷Rg1通过Akt/eNOS信号调控尼古丁胁迫下人牙周膜细胞的增殖和迁移

目的:探讨人参皂苷Rg1对尼古丁胁迫下的人牙周膜细胞(human periodontal ligament cells,HPDLCs)增殖和迁移的影响及分子机制.方法:采用组织块法分离培养HPDLCs,尼古丁(500 ng/mL)胁迫培养细胞7d.第3天分别进行人参皂苷Rg1 (0.01 μmol/L)处理、人参皂苷Rg1与PI3K抑制剂LY294002 (0.5 μmol/L)共处理、人参皂苷Rg1与Akt抑制剂Tricirbine(5μmol/L)共处理、人参皂苷Rg1与eNOS抑制剂L-NAME(1 mmol/L)共处理(Rg1+L-NAME组),持续处理至第7天.采用MTT法和Transwell法检测各处理组HPDLCs活力变化和细胞迁移率,并使用实时定量PCR与Western印迹法检测PI3K/Akt/eNOS信号蛋白变化,采用SPSS20.0软件包对数据进行统计学分析.结果:尼古丁抑制HPDLCs的增殖和迁移并显著上调PI3K表达,抑制Akt和eNOS表达;人参皂苷Rg1减缓尼古丁对细胞增殖和迁移抑制作用以及尼古丁对Akt和eNOS表达的抑制作用;Trieirbine与L-NAME衰减人参皂苷Rg1对尼古丁的抑制作用.结论:人参皂苷Rg1通过Akt/eNOS信号调控尼古丁胁迫下HPDLCs的增殖和迁移.     

Role of nitric oxide in matrix remodeling in diabetes and heart failure

Accumulation of oxidized-matrix between the endothelium and myocytes is associated with endocardial endothelial (EE) dysfunction in diabetes and heart failure. High levels of circulating homocysteine (Hcy) have been demonstrated in diabetes mellitus (DM). These high levels of Hcy (hyperhomocysteinemia, HHcy) have a negative correlation with peroxisome proliferator activated receptor (PPAR) expression. Studies have demonstrated that Hcy decreases bioavailability of endothelial nitric oxide (eNO), generates nitrotyrosine, and activates latent matrix metalloproteinase (MMP), instigating EE dysfunction. PPAR ligands ameliorate endothelial dysfunction and DM. In addition Hcy competes with PPAR ligands. The understanding of molecular, cellular, and extracellular mechanisms by which Hcy amplifies DM will have therapeutic ramifications for diabetic cardiomyopathy.     

雄激素对大鼠脑缺血/再灌注损伤后脑内顶叶皮层eNOS及iNOS表达的影响

目的探讨雄激素对大鼠脑缺血/再灌注（I/R）损伤后,脑内内皮型一氧化氮合酶（eNOS）和诱生型一氧化氮合酶（iNOS）表达的影响。方法将大鼠45只随机均分为去势组、雄激素组和假手术组,喂养2周后,各组再按照I/R后不同时间点分为6,24和72 h 3个亚组,共9组,每组均5只。采用W estern b lot检测不同处理组脑内顶叶皮层中eNOS和iNOS表达的变化。结果随着再灌注时间的延长,各组大鼠eNOS的表达水平均有下降的趋势;而去势组和假手术组大鼠iNOS表达的水平均有上升的趋势。与假手术组相比,再灌注各时间点雄激素处理组eNOS的水平显著升高（P<0.01）,去势组大鼠eNOS的水平明显降低（P<0.05）。而iNOS的表达水平则呈现出相反的趋势:即雄激素处理组明显低于正常水平（P<0.05）;而去势组大鼠则显著升高（P<0.05）。结论脑I/R后,在雄激素存在的情况下,eNOS的表达水平升高,而iNOS的表达水平降低;去势组eNOS的表达水平下降,而iNOS的表达水平上升,提示雄激素对脑I/R损伤可能具有保护作用。