Ataxias are rare diseases and the etiologic heterogeneity make individual entities even rarer. There are still substantial numbers of patients who are still poorly understood. Available assessment techniques still point to large numbers of patients needed for clinical trials and the need for cooperative efforts, better assessment tools and novel trial designs. Better understanding of neural circuitry abnormalities may lead to more effective symptomatic therapy. Opportunities exist for targeting at risk individuals for effective therapies but how this can be done is not clear. Preventive strategies may become feasible in many ataxias.

Substantial in vitro and in vivo evidence of neurotrophic and neuroprotective effects of lithium suggests that it may also have considerable potential for the treatment of neurodegenerative conditions. Lithium's main mechanisms of action appear to stem from its ability to inhibit glycogen synthase kinase-3 activity and also to induce signaling mediated by brain-derived neurotrophic factor. This in turn alters a wide variety of downstream effectors, with the ultimate effect of enhancing pathways to cell survival. In addition, lithium contributes to calcium homeostasis. By inhibiting N-methyl-D-aspartate receptor-mediated calcium influx, for instance, it suppresses the calcium-dependent activation of pro-apoptotic signaling pathways. By inhibiting the activity of phosphoinositol phosphatases, it decreases levels of inositol 1,4,5-trisphosphate, a process recently identified as a novel mechanism for inducing autophagy. These mechanisms allow therapeutic doses of lithium to protect neuronal cells from diverse insults that would otherwise lead to massive cell death. Lithium, moreover, has been shown to improve behavioral and cognitive deficits in animal models of neurodegenerative diseases, including stroke, amyotrophic lateral sclerosis, fragile X syndrome, and Huntington's, Alzheimer's, and Parkinson's diseases. Since lithium is already FDA-approved for the treatment of bipolar disorder, our conclusions support the notion that its clinical relevance can be expanded to include the treatment of several neurological and neurodegenerative-related diseases.

Objective To observe the expression distribution of bone morphogenetic proteins (BMP) in the spinal cord of normal adult rats. Methods Expression of BMP2, BMP4, and BMP7, and their receptors BMPR Ⅰa, BMPR Ⅰb, and BMP Ⅱ were detected by immunochemistry analysis in the spinal cord of normal adult rats. Results Expression of BMPR Ia or BMPR Ib was observed in the motor neurons of the anterior horn, sensory neurons of the dorsal horn, oligodentrocytes, some microglia, and some astrocytes. Expression of receptor BMPR Ⅱ was found in the oligodentrocytes and motor neurons in the gray matter of anterior horn. It was also expressed in some glial fibrillary acidic protein (GFAP)-positive astrocytes in the white matter but not in the gray matter. BMP2 and BMP4 were not expressed in the spinal cord of normal adult rats by immunohistochemistry. BMP7 was expressed in all the APC-positive oligodentrocytes, all the NeuN-positive motor neurons in the anterior horn, and some astrocytes in the normal spinal cord. Phosphated pSmad 1/5/8 protein was expressed in all the oligodentrocytes, all the neurons, and some astrocytes, especially in the GFAP-positive astrocytes which were RC2-positive radial glia in the subventricular zone.Conclusion BMP7, BMP receptors, and phosphated pSmad 1/5/8 are expressed in many types of cells whereas BMP2 and BMP4 are not expressed in the spinal cord of normal adult rats, which suggests an important function of BMP signal pathway in the neuron and glia of spinal cord.

Objective To determine the maintenance and loss of Epstein-Barr virus (EBV) genome during the clonal expansion of the EBV-infected epithelial cells. Methods The epithelial tumor cell line, 293-EBV, in which the EBV genome was observed with green fluorescent protein (GFP) readout. After a dozen of passages, it contained cells with strong or weak GFP expression, and some with complete loss of EBV genome. The cell growth was then continuously observed under a confocal microscope. The cell dividing and GFP expression were also observed during the clonal expansion by being made into very low density. Results The cells moved around due to adherence and mobility, while the GFP expression remained unchanged in the undivided cells. The cells could form compact or loosen clones. The EBV genome easily persisted in those clones when cells were growing compactly. As the cell number increased, the GFP expression became weak or even died away at the sites of low density in the loosen clones. Conclusion EBV-positive epithelial cells are able to sustain the EBV genome during its clonal expansion. The cells maintain EBV genomes by passing them to the daughter cells after replication. When the cells unsuccessfully inherit the EBV genome, the daughter cells may lose them which is related to the low cell density as well as the epithelial environment.

Cardiac fibroblasts play a pivotal role in cardiac remodeling.In response to various pro-fibrotic stimuli,such as pro-inflammatory cytokines,anoxia-reoxygenation and pressure overload as well as aging,cardiac fibroblasts undergo proliferation,migration and activation,leading to the accumulation of extracellular matrix components and increased thickness and stiffness of heart.The ligands for peroxisome proliferator-activated receptor γ,especially thiazolidinediones,modulate the function of cardiac fibroblasts and the progression of cardiac remodeling,especially under pathological conditions.Unfortunately these agents have not been found to be consistently beneficial in heart failure.Although the precise intracellular signaling pathways are not fully understood,existing evidence strongly supports the involvement of oxidative stress and related signaling pathways.Further,peroxisome proliferator-activated receptor γ and lectin-like oxidized low-density lipoprotein receptor-1 together play critical roles in thiazolidinediones-modulated cardiac fibroblast dysfunction.

The organic cation transport systems were initially recognized in studies of renal elimination.A variety of endogenous and exogenous compounds that are harmful to the body are eliminated from the kidney via glomerular filtration and/or active tubular secretion.Among those compounds are polar organic cations that require a transporter-mediated process to cross cellular membrane and be eventually excreted into the urine.The organic cation transport systems in the kidney have been recognized for several decades.Following the insight gained from the kidney,organic cation transporters (OCTs) have also been characterized in other tissues.In particular,the OCTs in the liver and in the intestine have been proposed as important determinants of drug absorption and disposition.Over the past several decades,the mechanisms of organic cation transport have been extensively characterized using in vivo models,ex vivo organ perfusions,in vitro tissue preparations and cell lines.In particular,the molecular cloning and characterization of OCTs have remarkably increased our knowledge of this important subfamily of solute carriers.In this article,we first review the molecular cloning and characterization of OCTs.We will then describe their transport mechanisms,tissue distribution and localization,and their specificity of interaction with organic cations.Regulatory mechanisms and genetic animal models will be reviewed as they provide the most important insight on this class of transporters in recent years.Finally,we will summarize genetic variation in human OCT genes and raise clinical perspectives on these important transporters.

To examine the occurrence of neuron activation,neurodegeneraion and cell death,and the correlation among them in the hippocampus after status epilepticus.Methods CFV,Fluoro Jade B and c-Fos staining were done at multiple time points after pilocarpine induced status epilepticus.Results In the stratum granulosum of dentate gyrus,c-Fos positive neurons increased significantly at 1 h,2 h and 1 d after status epilepticus (P ＜0.01 or 0.05).However,almost no Fluoro Jade B staining cell was found in the stratum granulosum in the experiment and control groups,and no obvious difference was shown on the numbers of CFV staining cells in this area among all groups.In the hilus of dentate gyrus of different groups,there were no c-Fos positive neurons in all groups.In the hilus,the number of Fluoro Jade B staining cells significantly increased at 2 h and 1 d after the status epilepticus (P ＜0.01 ),and the number of CFV staining neurons dramatically decreased 1 d after the status epilepticus ( P ＜ 0.01 ) compared with the control.In the stratum pyramidale of CA1,the numbers of c-Fos positive neurons at 30 mim,1 h,2 h and 1 d,and Fluoro Jade B staining cells at 2 h and 1 d after the status epilepticus significantly increased (P ＜ 0.01 or 0.05 ),while no obvious difference in the number of CFV staining cells in the stratum pyramidale of CA1 among different groups was shown.Conclusion There is no direct correlation among cell activation,neuron degeneration and cell death in the hippocampus of mice after pilocarpine induced status epilepticus.

Objective:To determine the antioxidization and antiproliferation of extract from leaves of Toona sinensis (LTS).Methods:The total phenolic extract of LTS was obtained by solvent and polyamide resin to determine the content.The antioxidization of the LTS extract was measured by TOSC assay.Antiproliferation was studied in vitro with different human cancer cells.Results:The total phenolic content in the LTS was (427.53±4.31) mg/g and antioxidization was 807.64 μmoL vitamin C equivalents/g in the sample.The extract significantly inhibited the colon cancer cell Caco-2,human liver cancer cell HepG2 and breast cancer cell MCF-7 proliferation with EC50 (4.00±0.39),(153.16±13.49) and (193.46±14.68) μg/mL,respectively.The bioactivity index (BI) of the LTS extract was nearly 283.Caco-2 was more sensitive than MCF-7 and HepG2.Conclusion:Extract from LTS has anticancer properties useful for preventing chronic diseases.

Objective:To identify proteins associated with nasopharyngeal carcinoma (NPC) metastasis,and provide scientific basis for the prevention and cure of NPC.Methods:A two-dimensional gel electrophoresis and mass spectrometry were performed to screen for differential proteins between highly metastatic 5-8F and non-metastatic 6-10B NPC cell lines.Western blot was used to confirm the differential proteins.We used siRNA to inhibit the expression of differential protein nm23-H1 to determine the association of nm23-H1 with NPC in vitro invasive ability.Immunohistochemistry and statistics were used to evaluate the correlation of nm23-H1 expression with clinicopathological features and clinical outcomes in paraffin-embedded archival tissues including 93 cases of primary NPC and 20 cases of cervical lymphonode metastatic NPC (LMNPC).Results:A total of 15 differential proteins in the 2 cell lines were identified by a proteomic approach,and 3 differential proteins were selectively confirmed.Downregulation of nm23-H1 by siRNA significantly increased the in vitro invasive ability of 6-10B.Significant nm23-H1 downregulation was observed in LMNPC compared with primary NPC.nm23-H1 downregulation in primary NPC was positively correlated with lymphonode and distant metastasis,advanced clinical stage and recurrence.Survival curves showed that patients with nm23-H1 downregulation in primary NPC had a poor prognosis.Multivariate analysis confirmed that nm23-H1 expression level in primary NPC was an independent prognostic indicator.Conclusion:nm23-H1 behaves as a metastasis suppressor in NPC,and nm23-H1 downregulation is a biomarker for poor NPC prognosis.

Objective:Hepatic stellate cells (HSCs) are the principal cells responsible for the development of hepatic fibrosis and cirrhosis.During the fibrotic process,HSCs undergo proliferation and transdifferentiation from a quiescent to myofibroblast-like phenotype.The fate of myofibroblastlike HSCs includes apoptosis or reversion back to a quiescent phenotype.The mechanisms involved in the apoptotic process of HSCs have yet to be determined.The purpose of the present study is to determine the effects of extracellular signal-regulated kinases (ERKs) phosphorylation on the apoptosis of HSCs induced by staurosporine.Methods:We used Western blot and flow cytometry to detect the expression level of ERK and cell apoptosis status in four rat hepatic stellate cell lines (CFSC-8B,-2G,-3H and -5H).Results:Each hepatic stellate cell line had a distinct morphology consistent with their expression level of α-SMA and that CFSC-8B cells had the highest α-SMA expression.Although all four cell types expressed similar levels of ERK1/2,phosphorylation levels were significantly higher in CFSC8B and CFSC-2G than in CFSC-3H and CFSC-5H cells.When CFSC-8B ceils (high ERK1/2 phosphorylation) and CFSC-5H cells (low ERK1/2 phosphorylation) were employed to examine staurosporine-induced apoptosis,CFSC-8B cells were significantly more sensitive.Staurosporine further increased ERK1/2 phosphorylation in both cell lines.Conclusion:ERK1/2 phosphorylation in HSCs determines the sensitivity of HSCs to staurosporine-induced apoptosis.