Lithium is one of the most widely used mood-stabilizing agents for the treatment of bipolar disorder. Although the underlying mechanism(s) of this mood stabilizer remains controversial, recent evidence linking lithium to neurotrophic/neuroprotective effects (Choi and Sung (2000) 1475, 225-230; Davies et al. (2000) 351, 95-105) suggests novel benefits of this drug in addition to mood stabilization. Here, we report that both lithium as well as valproic acid (VPA) inhibit beta-amyloid peptide (Abeta) production in HEK293 cells stably transfected with Swedish amyloid precursor protein (APP)(751) and in the brains of the PDAPP (APP(V717F)) Alzheimer's disease transgenic mouse model at clinically relevant plasma concentrations. Both lithium and VPA are known to be glycogen synthase kinase-3 (GSK3) inhibitors. Our studies reveal that GSK3beta is a potential downstream kinase, which modulates APP processing because inhibition of GSK3 activity by either a dominant negative GSK3beta kinase-deficient construct or GSK3beta antisense oligonucleotide mimics lithium and VPA effects. Moreover, lithium treatment abolished GSK3beta-mediated Abeta increase in the brains of GSK3beta transgenics and reduced plaque burden in the brains of the PDAPP (APP(V717F)) transgenic mice.
Extracts from Petasites hybridus were found to inhibit peptido-leukotriene biosynthesis in isolated peritoneal macrophages. Chemical analysis by gas chromatography coupled with mass and infrared spectroscopy facilitated the identification of three isomeric oxopetasan esters, petasin, and isopetasin as the main compounds of these extracts. Fractionations obtained by column chromatography of the most effective extract indicated a correlation between peptido-leukotriene biosynthesis inhibition and the content of isopetasin, a sesquiterpene ester of isopetasol and angelic acid, as well as the isomeric oxopetasan esters. Petasin, a structural isomer of isopetasin, however, was found to be inactive. It may even reduce the peptido-leukotrine inhibitory effect of isopetasin. It is concluded that isopetasin and the oxopetasan esters in Petasites hybridus inhibit the biosynthesis of the vasoconstrictive peptido-leukotrienes. This effect may contribute to some of the medicinal properties of Petasites hybridus extracts such as, e.g., gastroprotection and spasmolytic activity.
In a search for novel growth factors, we discovered that human interleukin-20 (IL-20) enhanced colony formation by CD34 ؉ multipotential progenitors. IL-20 had no effect on erythroid, granulocyte-macrophage, or megakaryocyte progenitors. IL- IntroductionCytokines are important regulators of the growth and development of hematopoietic cells 1,2 ; some are currently in clinical use. In a search for novel factors that regulate hematopoiesis, colony assays were used to screen novel secreted proteins identified through bioinformatics. One protein identified was identical to . 3,4 We demonstrate that IL-20 specifically enhances the proliferation of multipotential progenitors in vitro and in vivo without effect on more lineage-restricted progenitor cells. Study design Protein productionRecombinant human , containing a C-terminal FLAG tag (Eastman Kodak, Rochester, NY) followed by 6 histidine residues (Flis), was produced in 293EBNA1 cells. 5 We captured rhIL-20-Flis on Pharmacia Chelating Sepharose FF (Amersham-Pharmacia, Piscataway, NJ). The endotoxin level was less than 5.3 EU/mg rhIL-20. Colony assays for human and murine progenitorsCD34 ϩ human bone marrow or cord blood cells were purchased from BioWhittaker (Walkersville, MD). Colony assays for granulocytemacrophage (CFU-GM), erythroid (BFU-E), and multipotential (CFU-GEMM) progenitors were as described. 6,7 Megakaryocyte (CFU-Meg) progenitor assays were carried out using MegaCult-C medium (Stem Cell Technologies, Vancouver, BC, Canada). IL-20 transgenic miceTransgenic (TG) mice were generated by established techniques. 8 Human IL-20 was overexpressed in TG mice using apolipoprotein E gene promoter. IL-20 levels in mouse serum were determined using enzyme-linked immunosorbent assay (ELISA) with antihuman rhIL-20. rhIL-20 administration to normal miceFemale BDF1 mice (8-10 weeks of age; Harlan, Indianapolis, IN) were administered rhIL-20 (5 g/mouse) subcutaneously twice a day for 10 days. At day 11, mice were killed, bone marrow and spleen cells were counted, cells were used for colony assays, and the proportion of progenitors in S-phase of the cell cycle was estimated. 7,9,10 Results and discussion IL-20 in vitroIL-20 did not stimulate colony formation, but it increased the numbers of larger-sized colonies in combination with recombinant human stem cell factor (SCF) and erythropoietin (EPO) ( Figure 1Ai-ii). Colonies cultured with IL-20 contained cells with and without hemoglobin expression. Microscopic examination of 22 individual large colonies stained with Wright-Giemsa revealed mainly erythroblasts mixed with megakaryocytes. Granulocytes and monocytes were also detected (original magnification, ϫ 400) within these colonies but were less prominent than erythroblasts and megakaryocytes . This suggested that IL-20 enhanced CFU-GEMM.Colony assays were performed with human bone marrow (BM) and cord blood (CB) CD34 ϩ cells using various cytokine combinations. IL-20 (200 ng/mL), in combination with EPO and SCF, significantly enhanced BM CFU-GEMM numbers approximate...
PTH has been shown to enhance fracture repair; however, exactly when and where PTH acts in this process remains to be elucidated. Therefore, we conducted a longitudinal, region-specific analysis of bone regeneration in mature, osteopenic rats using a cortical defect model. Six-month-old rats were ovariectomized, and allowed to lose bone for 2 months, before being subjected to bilateral 2-mm circular defects in their femoral diaphyses. They were then treated for 5 wk with hPTH1-38 at doses of 0, 3, 10, or 30 microg/kg . d and scanned weekly by in vivo quantitative computed tomography. Quantitative computed tomography analyses showed temporal, dose-dependent increases in mineralization in the defects, intramedullary (IM) spaces, and whole diaphyses at the defect sites. Histomorphometry confirmed PTH stimulation of primarily woven bone in the defects and IM spaces, but not the periosteum. After necropsy, biomechanical testing identified an increase in strength at the highest PTH dose. Serum procollagen type I N-terminal propeptide concentration showed a transient increase due to drilling, but procollagen type I N-terminal propeptide also increased with PTH treatment, whereas tartrate-resistant acid phosphatase unexpectedly decreased. Analyses of lumber vertebra confirmed systemic efficacy of PTH at a nonfracture site. In summary, PTH dose dependently induced new bone formation within defects, at endocortical surfaces, and in IM spaces, resulting in faster and greater bone healing, as well as efficacy at other skeletal sites. The effects of PTH were kinetic, region specific, and most apparent at high doses that may not be entirely clinically relevant; therefore, clinical studies are necessary to clarify the therapeutic utility of PTH in bone healing.
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