Neuroactive steroids: State of the art and new perspectives

Neuroactive steroids include synthetic steroidal compounds and endogenous steroids, produced by endocrine glands (hormonal steroids) or the nervous tissue (neurosteroids), which regulate neural functions. These steroids bind to nuclear receptors or act through the activation of membrane-associated signaling pathways to modulate various important processes including the development of the nervous system, neural plasticity and the adaptive responses of neurons and glial cells under pathological conditions. Reviewed and updated in the present paper are the pleiotropic and protective abilities of neuroactive steroids. The fundamental evidence and knowledge gained constitute a profound background that offers interesting possibilities for developing effective strategies against several disorders of the nervous system. Received 3 September 2007; received after revision 24 October 2007; accepted 29 October 2007     

Mitochondrial association of alpha-synuclein causes oxidative stress

α-Synuclein is a neuron-specific protein that contributes to the pathology of Parkinson’s disease via mitochondria-related mechanisms. The present study investigated possible interaction of α-synuclein with mitochondria and consequences of such interaction. Using SHSY cells overexpressing α-synuclein A53T mutant or wild-type, as well as isolated rat brain mitochondria, the present study shows that α-synuclein localizes at the mitochondrial membrane. In both SHSY cells and isolated mitochondria, interaction of α-synuclein with mitochondria causes release of cytochrome c, increase of mitochondrial calcium and nitric oxide, and oxidative modification of mitochondrial components. These findings suggest a pivotal role for mitochondria in oxidative stress and apoptosis induced by α-synuclein. Received 27 December 2007; received after revision 7 February 2008; accepted 8 February 2008     

Modulation by polyamines of apoptotic pathways triggered by procyanidins in human metastatic SW620 cells

We showed previously that inhibition of polyamine catabolism with the polyamine oxidase inhibitor MDL 72527 (MDL) potentiates the apoptotic effects of apple procyanidins (Pcy) in SW620 cells. Here we report that Pcy caused an activation of the intrinsic apoptotic pathway through enhanced polyamine catabolism and mitochondrial membrane depolarization. MDL in the presence of Pcy caused a profound intracellular depletion of polyamines and exerted a protective effect on mitochondrial functions. MDL potentiation of Pcy-triggered apoptosis was reversed by addition of exogenous polyamines. In addition, MDL in combination with Pcy activated the extrinsic apoptotic pathway through enhanced TRAIL-death receptor (DR4/DR5) expression. Potentiation of Pcy-triggered apoptosis by MDL was inhibited when cells were exposed to specific inhibitors of DR4/DR5. These data indicate that the depletion of intracellular polyamines by MDL in the presence of Pcy caused a switch from intrinsic to extrinsic apoptotic pathways in human colon cancer-derived metastatic cells. Received 15 January 2008; received after revision 19 February 2008; accepted 7 March 2008     

Mitochondrial permeability transition triggers the release of mtDNA fragments

Fragments of mitochondrial DNA are released from mitochondria upon opening of the mitochondrial permeability transition pore. Cyclosporin A, an inhibitor of pore opening, completely prevented the release of mitochondrial fragments. Induction of mitochondrial permeability transition and subsequent release of the fragments of mitochondrial DNA could be one cause of genomic instability in the cell.Received 22 September 2004; received after revision 11 October 2004; accepted 18 October 2004M. Patrushev, V. Kasymov and V. Patrusheva contributed equally to this work.     

运动与线粒体关系的研究进展

运动可导致线粒体发生形态和生理生化指标的变化，不同的运动可引起不同的变化．从有氧运动和大强度力竭运动两个方面综述了线粒体的形态学与生理生化指标的变化，并报道了线粒体损伤的保护和预防，以及基因选材的一些研究现状．     

钙调素参与植物线粒体琥珀酸脱氢酶（SDH）活性调节的研究

对纯化的玉米线粒体ＳＤＨ进行ＣａＭ含量测定电泳分析，对ＮＡＤＫ的激活及外源ＣａＭ对ＳＤＨ活性的影响研究，结果表明：ＳＤＨ中可能含ＣａＭ亚基，并且ＳＤＨ活性可能受Ｃａ（２＋）·ＣａＭ调节．     

丁丙诺啡对小鼠中脑导水管周围灰质Ca~(2)分布的影响:电镜及电子探针研究

用透射电镜及电子探针X-射线显微分析法研究了丁丙诺啡(Buprenorphine,BN)引起镇痛期间小鼠中脑导水管周围灰质区钙离子分布的改变.按照改进的Komnick方法,脑组织用含有2％焦锑酸钾的1％锇酸固定.实验结果表明,动物经腹腔注射BN(0.8mg/kg)30分钟后,在髓鞘、轴突、线粒体和细胞核中均可见到电子致密的沉淀颗粒,尤其在髓鞘的环状片层中形成大量的、密集的颗粒状沉淀.电子探针X-射线显微分析证实髓鞘中的沉淀颗粒含有元素钙,提示BN镇痛时髓鞘结合大量的钙离子,并且可能经过髓鞘的转运,钙离子进入轴突,贮存于线粒体中.本文讨论了在中枢神经系统中的钙离子转运的可能途径.     

原花青素对•OH致损的鼠肝线粒体的保护作用

采用分光光度法和荧光偏振法，检测了原花青素对•OH引起的鼠肝线粒体损伤的保护作用.结果表明，原花青素能有效增加受损伤的线粒体的膜脂流动性，明显减少受损伤的线粒体肿胀及脂质过氧化物的形成,从而维护线粒体结构和功能的完整性.以上结果为原花青素的进一步开发提供了新的资料.     

The interaction of superoxide with nitric oxide destabilizes hypoxia-inducible factor-1α

In renal carcinoma cells (RCC4) hypoxia inducible factor-1 (HIF-1) is constitutively expressed due to a von Hippel Lindau protein deficiency, but can be degraded by calpain, independently of the 26S proteasome, when exposed to hypoxia/nitric oxide (NO). In this study we examined molecular mechanisms to explain calpain activation. The inability of hypoxia/NO to degrade HIF-1α in respiratory-deficient RCC4-ρ0 cells pointed to the requirement for mitochondria-derived reactive oxygen species. A prerequisite for O ₂ ⁻ in combination with NO to destabilize HIF-1α was corroborated in RCC4-p0 cells, when the redox cycler 2,3-dimethoxy-1,4-naphthoquinone was used as a source of superoxide. Degradation of HIF-1α required intracellular calcium transients and calpain activation. Using uric acid to interfere with signal transmission elicited by NO/O ₂ ⁻ blocked HIF-1α degradation and attenuated a calcium increase. We conclude that an oxidative signal as a result of NO/O ₂ ⁻ coformation triggers a calcium increase that activates calpain to degrade HIF-1α, independently of the proteasome. Received 14 August 2007; received after revision 4 October 2007; accepted 22 October 2007     

Chronic gestational exposure to ethanol impairs insulin-stimulated survival and mitochondrial function in cerebellar neurons

Chronic gestational exposure to ethanol has profound adverse effects on brain development. In this regard, studies using in vitro models of ethanol exposure demonstrated impaired insulin signaling mechanisms associated with increased apoptosis and reduced mitochondrial function in neuronal cells. To determine the relevance of these findings to fetal alcohol syndrome, we examined mechanisms of insulin-stimulated neuronal survival and mitochondrial function using a rat model of chronic gestational exposure to ethanol. In ethanol-exposed pups, the cerebellar hemispheres were hypoplastic and exhibited increased apoptosis. Isolated cerebellar neurons were cultured to selectively evaluate insulin responsiveness. Gestational exposure to ethanol inhibited insulin-stimulated neuronal viability, mitochondrial function, Calcein AM retention (membrane integrity), and GAPDH expression, and increased dihydrorosamine fluorescence (oxidative stress) and pro-apoptosis gene expression (p53, Fas-receptor, and Fas-ligand). In addition, neuronal cultures generated from ethanol-exposed pups had reduced levels of insulin-stimulated Akt, GSK-3β, and BAD phosphorylation, and increased levels of non-phosphorylated (activated) GSK-3β and BAD protein expression. The aggregate results suggest that insulin-stimulated central nervous system neuronal survival mechanisms are significantly impaired by chronic gestational exposure to ethanol, and that the abnormalities in insulin signaling mechanisms persist in the early postnatal period, which is critical for brain development. Received 21 January 2002; received after revision 28 February 2002; accepted 25 March 2002