Poly-L-ornithine blocks the inhibitory effects of fibronectin on oligodendrocyte differentiation and promotes myelin repair.

The extracellular matrix surrounding oligodendrocytes plays an important role during myelination and remyelination in the brain. In many cases, the microenvironment surrounding demyelination lesions contains inhibitory molecules, which lead to repair failure. Accordingly, blocking the activity of these inhibitory factors in the extracellular matrix should lead to more successful remyelination. In the central nervous system, oligodendrocytes form the myelin sheath. We performed primary cell culture and found that a natural increase in fibronectin promoted the proliferation of oligodendrocyte progenitors during the initial stage of remyelination while inhibiting oligodendrocyte differentiation. Poly-L-ornithine blocked these inhibitory effects without compromising fibronectin's pro-proliferation function. Experiments showed that poly-L-ornithine activated the Erk1/2 signaling pathway that is necessary in the early stages of differentiation, as well as PI3K signaling pathways that are needed in the mid-late stages. When poly-L-ornithine was tested in a lysolecithin-induced animal model of focal demyelination, it enhanced myelin regeneration and promoted motor function recovery. These findings suggest that poly-L-ornithine has the potential to be a treatment option for clinical myelin sheath injury.

Ankfy1 Is Involved in the Maintenance of Cerebellar Purkinje Cells.

Purkinje cells are critical for the function of cerebellum. The degeneration of Purkinje cells leads to defects in motion control. We have found that Purkinje cells specifically express Ankfy1 protein during development and in adult. This protein seems to play minor functions during development as Ankfy1 knockout mice appear normal till adult. However, at 9-month-old, knockout mice showed abnormal cerebellum with reduced vermis size and developed defective motor function. Further investigation demonstrated that the cerebellum of the mutant mouse has lost most of its Purkinje cells, while other cerebellar cells remained largely normal. Our data suggested that the Ankfy1 might be important for the maintenance of cerebellar Purkinje cells.

Effects of the extracellular matrix on myelin development and regeneration in the central nervous system.

Extracellular matrix (ECM) is a collection of extracellular molecules secreted by cells, providing structural and biochemical support for surrounding tissues. The ECM exerts biological effects by interacting with growth factors, signal receptors or adhesion molecules. In the case of myelin formation and regeneration, the combination of ECM and its receptors (for example, integrins) modulates signaling pathways such as PI3K, MAPK, etc., which in turn induces complex biological effects throughout various stages of myelination and regeneration. Studies have also found that myelin injury would cause changes in ECM composition and thus affecting the myelin regeneration process. Research on the ECM will provide a better understanding of how myelin is formed and regenerated, which will help to develop new therapies for demyelinating diseases. Future progress in this field will provide important information on how to modify the ECM to promote proliferation and differentiation of oligodendrocyte precursor cells (OPC), thereby stimulating myelin formation and regeneration and restoring normal neural function.

Protein Kinase CK2, a Potential Therapeutic Target in Carcinoma Management

The Protein kinase CK2 (formerly known as casein kinase 2) is a highly conserved serine/ threonine kinase overexpressed in various human carcinomas and its high expression often correlates with poor prognosis. CK2 protein is localized in the nucleus of many tumor cells and correlates with clinical features in many cases. Increased expression of CK2 in mice results in the development of various types of carcinomas (both solids and blood related tumors, such as (breast carcinoma, lymphoma, etc), which reveals its carcinogenic properties. CK2 plays essential roles in many key biological processes related to carcinoma, including cell apoptosis, DNA damage responses and cell cycle regulation. CK2 has become a potential anti-carcinoma target. Various CK2 inhibitors have been developed with anti-neoplastic properties against a variety of carcinomas. Some CK2 inhibitors have showed good results in in vitro and pre-clinical models, and have even entered in clinical trials. This article will review effects of CK2 and its inhibitors on common carcinomas in in vitro and pre-clinical studies.

LINC00461, a long non-coding RNA, is important for the proliferation and migration of glioma cells.

An increasing number of reports have revealed that long non-coding RNAs are important players in tumorigenesis. Here we showed that long non-coding RNA LINC00461 is highly expressed in glioma tissues compared to non-neoplastic brain tissues. The knockdown of LINC00461 suppressed cyclinD1/A/E expression which led to G0/G1 cell cycle arrest and inhibited cell proliferation in glioma cells. LINC00461 suppression also inhibited glioma cell migration and invasion. The function of LINC00461 in glioma cells is partially mediated by MAPK/ERK and PI3K/AKT signaling pathways as down-regulation of LINC00461 expression suppressed ERK1/2 and AKT activities. Moreover, LINC00461 knockdown decreased expression levels of microRNA miR-9 and flanking genes MEF2C and TMEM161B. Taken together, our results demonstrate that LINC00461 is important for glioma progression affecting cell proliferation, migration and invasion via MAPK/ERK, PI3K/AKT, and possibly other signaling pathways.

Molecular biology of glioblastoma: Classification and mutational locations.

Glioblastomas are regarded as the most common malignant brain tumours with great morphological and genetical heterogeneity. They comprise 12% to 15% of all intracranial tumours, with its peak observed in the 8th decade of life. The five-year survival is only 5%. Primary glioblastomas are more common in elders while secondary glioblastomas mostly involve younger people. Based upon gene expression profile, researchers have classified glioblastomas into several subtypes. Genetic mutations provide an advanced standard platform essential for diagnosis, therapeutic remedies and prognosis of glioblastomas. Common mutations observed in glioblastomas are loss of heterozygosity at 10q followed by epidermal growth factor receptor amplification (34%) and others. Vascular occlusion model and tumour stem cell model can explain the possible mechanism in glioblastomas pathogenesis. This review highlights glioblastomas' classifications, genetic mutations, pathogenesis and prognosis of different sub-types.

In vitro activity of new artemisinin derivatives against Plasmodium falciparum clinical isolates from Gabon.

Nowadays, artemisinins are the mainstay of malaria treatment, but initial indications of resistance against clinically used derivatives are present. In this study, ten new artemisinin derivatives were tested in vitro against Plasmodium falciparum laboratory strains as well as clinical isolates from Gabon. All derivatives were highly active, with 50% inhibitory concentrations (IC(50) values) <13 nM in the clinical isolates. The activity of one fluoro-containing derivative did not correlate with that of the parent compound, suggesting a different activity profile. New artemisinin derivatives with different activity profiles are of special interest as they represent an important class of candidates for pre-clinical testing in clinical parasite isolates adapted to currently used artemisinins, since derivatisation is one possible strategy to prolong the clinical usefulness of this important class of antimalarials.

Design of novel artemisinin-like derivatives with cytotoxic and anti-angiogenic properties.

Artemisinins are plant products with a wide range of medicinal applications. Most prominently, artesunate is a well tolerated and effective drug for treating malaria, but is also active against several protozoal and schistosomal infections, and additionally exhibits anti-angiogenic, anti-tumorigenic and anti-viral properties. The array of activities of the artemisinins, and the recent emergence of malaria resistance to artesunate, prompted us to synthesize and evaluate several novel artemisinin-like derivatives. Sixteen distinct derivatives were therefore synthesized and the in vitro cytotoxic effects of each were tested with different cell lines. The in vivo anti-angiogenic properties were evaluated using a zebrafish embryo model. We herein report the identification of several novel artemisinin-like compounds that are easily synthesized, stable at room temperature, may overcome drug-resistance pathways and are more active in vitro and in vivo than the commonly used artesunate. These promising findings raise the hopes of identifying safer and more effective strategies to treat a range of infections and cancer.

Two base pair duplexes suffice to build a novel material.

Tetrahedral DNA hybrids with tetrakis(p-hydroxyphenyl)methane cores hybridize in a sequence-specific fashion at much higher temperatures than isolated linear duplexes. Dinucleotide DNA arms suffice to induce the formation of a solid at room temperature; this demonstrates the strength of multivalent binding. The graphic shows a view of a modeled assembly.

Effect of artemisinins and other endoperoxides on nitric oxide-related signaling pathway in RAW 264.7 mouse macrophage cells.

Artemisinin is the active principle of the Chinese herb Artemisia annua L. In addition to its anti-malarial activity, artemisinin and its derivatives have been shown to exert profound anti-cancer activity. The endoperoxide moiety in the chemical structure of artemisinin is thought to be responsible for the bioactivity. Here, we analyzed the cytotoxicity and the ability of artemisinin, five of its derivatives, and two other endoperoxides to inhibit generation of nitric oxide (NO). In the RAW 264.7 mouse macrophage cell line, the well-established model cell line to analyze NO generation, artesunate revealed the highest ability to inhibit NO production among all compounds tested. In cytotoxicity assays (XTT assay), the IC(50) value of RAW 264.7 cells for artesunate was determined to be 3.1+/-0.7 microM. In order to associate the cytotoxic effects with specific alteration in gene expression related to NO metabolism and signaling, whole genome mRNA microarray analyses were conducted. RAW 264.7 cells were treated with artesunate using DMSO as vehicle control followed by microarray analysis. A total of 36 genes related to NO metabolism and signaling were found to be differentially expressed upon exposure to artesunate. Apart from NO-related genes, the expression of genes associated with other functional groups was also analyzed. Out of 24 functional groups, differential expression was most prominent in genes involved in cell-to-cell signaling and interactions. Further refinement of this analysis showed that the pathways for cAMP-mediated signaling and Wnt/beta-catenin signaling were most closely related to changes in mRNA expression. In conclusion, NO generation and signaling play a role in exhibiting cytotoxic activity of artesunate. In addition, other signaling pathways also contribute to the inhibitory effect of artesunate towards RAW 264.7 cells pointing to a multi-factorial mode of action of artesunate.

Optimization of an LC-MS method for the determination of artesunate and dihydroartemisinin plasma levels using liquid-liquid extraction.

Artesunate is a derivate of artemisinin, an antimalarial drug used for the treatment of malaria caused by Plasmodium falciparum and related parasites. Artesunate is hydrolyzed rapidly to dihydroartemisinin in vivo. It has been found that artemisinin and its derivatives may have neurotoxic effects. A method was developed to analyze human plasma samples for the contents of artesunate and dihydroartemisinin. The plasma samples are extracted with ethyl acetate, concentrated, and redissolved in water/acetonitrile. Analyses was performed with liquid chromatography-mass spectrometry using a binary gradient program with aquaeous formic acid and acetonitrile formic acid on a XTerra MS C18-column. The mass spectrometer was operated in the positive atmospheric pressure chemical ionization mode with single ion recording. The lower limits of detection were 10 and 25 ng/mL plasma for DHA and artesunate, respectively. The method was validated according to the guidelines for validation of bioanalytical methods.

Chemical instability determines the biological action of the artemisinins.

Artemisinin is a sesquiterpene compound of plant origin. It has a low molecular weight, and it contains five oxygen atoms, two in a lactone function, one is part of a seven membered ring system and two forms a peroxide function bridging over the seven-membered ring. It is a highly energetic molecule prone to lose its activity if circumstances permit. Reduction of its lactone function into dihydroartemisinin makes derivatization easy. Esterification and ether formation contribute to stability. Dihydroartemisinin exists preferably in a beta epimeric format but flip-flops with the alpha epimer. Solvation effects play a role. In doing so, open forms are created and they contribute to the instability, both of the peroxide and of the seven-membered ring. Artemisinins constitute a remarkable class of compounds which display instability both biologically and chemically due to the presence of various functional groups. Activity ranges from a wonderful action against a series of parasites, in particular malaria and schistosomiasis, to bacteria, fungi and selected viruses. The latest developments indicate a potential use in adjuvant cancer chemotherapy. The built-in chemical instability, necessary for biological action, causes serious pharmaceutical problems and only a restricted number of derivatives are useful. Problems are accelerated under tropical conditions and the basic active drug dihydroartemisinin cannot be used as such since it is prone to accelerated breakdown into a series of inactive products. The pitfalls of chemical instability and pharmaceutical stability are discussed in relation to the current uses of the drugs.