236 research outputs found
Okullarda düzenli aralıklarla gerçekleştirilen kontroller saç biti (pediculus capitis) İnsidansını düşürmekte yeterli olabilir mi?
Feconomics®: a simple, novel and fast technique for stool concentration in parasitology laboratory
Macrophage Mal1 Deficiency Suppresses Atherosclerosis in Low-Density Lipoprotein Receptor -Null Mice by Activating Peroxisome Proliferator-Activated Receptor-g-Regulated Genes
Cataloged from PDF version of article.Objective-The adipocyte/macrophage fatty acid-binding proteins aP2 (FABP4) and Mal1 (FABP5) are intracellular lipid chaperones that modulate systemic glucose metabolism, insulin sensitivity, and atherosclerosis. Combined deficiency of aP2 and Mal1 has been shown to reduce the development of atherosclerosis, but the independent role of macrophage Mal1 expression in atherogenesis remains unclear.
Methods and Results-We transplanted wild-type (WT), Mal1(-/-), or aP2(-/-) bone marrow into low-density lipoprotein receptor-null (LDLR(-/-)) mice and fed them a Western diet for 8 weeks. Mal1(-/-)-> LDLR(-/-) mice had significantly reduced (36%) atherosclerosis in the proximal aorta compared with control WT -> LDLR(-/-) mice. Interestingly, peritoneal macrophages isolated from Mal1-deficient mice displayed increased peroxisome proliferator-activated receptor-gamma (PPAR gamma) activity and upregulation of a PPAR gamma-related cholesterol trafficking gene, CD36. Mal1(-/-) macrophages showed suppression of inflammatory genes, such as COX2 and interleukin 6. Mal1(-/-)-> LDLR(-/-) mice had significantly decreased macrophage numbers in the aortic atherosclerotic lesions compared with WT -> LDLR(-/-) mice, suggesting that monocyte recruitment may be impaired. Indeed, blood monocytes isolated from Mal1(-/-)-> LDLR(-/-) mice on a high-fat diet had decreased CC chemokine receptor 2 gene and protein expression levels compared with WT monocytes.
Conclusion-Taken together, our results demonstrate that Mal1 plays a proatherogenic role by suppressing PPAR gamma activity, which increases expression of CC chemokine receptor 2 by monocytes, promoting their recruitment to atherosclerotic lesions. (Arterioscler Thromb Vasc Biol. 2011;31:1283-1290.
AT7519, a Novel Small Molecule Multi-Cyclin Dependent Kinase Inhibitor, Induces Apoptosis in Multiple Myeloma VIA GSK3 beta
Dysregulated cell cycling is a universal hallmark of cancer and is often mediated by abnormal activation of cyclin-dependent kinases (CDKs) and their cyclin partners. Overexpression of individual complexes are reported in multiple myeloma (MM), making them attractive therapeutic targets. In this study, we investigate the preclinical activity of a novel small-molecule multi-CDK inhibitor, AT7519, in MM. We show the anti-MM activity of AT7519 displaying potent cytotoxicity and apoptosis; associated with in vivo tumor growth inhibition and prolonged survival. At the molecular level, AT7519 inhibited RNA polymerase II (RNA pol II) phosphorylation, a CDK9, 7 substrate, associated with decreased RNA synthesis confirmed by [(3)H] Uridine incorporation. In addition, AT7519 inhibited glycogen synthase kinase 3beta (GSK-3beta) phosphorylation; conversely pretreatment with a selective GSK-3 inhibitor and shRNA GSK-3beta knockdown restored MM survival, suggesting the involvement of GSK-3beta in AT7519-induced apoptosis. GSK-3beta activation was independent of RNA pol II dephosphorylation confirmed by alpha-amanitin, a specific RNA pol II inihibitor, showing potent inhibition of RNA pol II phosphorylation without corresponding effects on GSK-3beta phosphorylation. These results offer new insights into the crucial, yet controversial role of GSK-3beta in MM and show significant anti-MM activity of AT7519, providing the rationale for its clinical evaluation in MM
Hepatobiliary scintigraphy in vasculitis of the gallbladder as a manifestation of polyarteritis nodosa: a case report
The JAK inhibitor AZD1480 regulates proliferation and immunity in Hodgkin lymphoma
Aberrant activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway has been reported to promote proliferation and survival of Hodgkin and Reed–Sternberg cells of Hodgkin lymphoma (HL). We investigated the activity of the JAK inhibitor AZD1480 in HL-derived cell lines and determined its mechanisms of action. AZD1480 at low doses (0.1–1 μ) potently inhibited STATs phosphorylation, but did not predictably result in antiproliferative effects, as it activated a negative-feedback loop causing phosphorylation of JAK2 and extracellular signal-regulated kinases 1 and 2 (ERK1/2), and increased IP-10, RANTES and interleukin (IL)-8 concentrations in the supernatants. Inhibition of the ERK activity by mitogen-activated extracellular signal regulated kinase (MEK) inhibitors (UO126 and PD98059) enhanced the cytotoxic activity of AZD1480. Interestingly, submicromolar concentrations of AZD1480 demonstrated significant immunoregulatory effects by downregulating T-helper 2 cytokines and chemokines, including IL-13 and thymus- and activation-regulated chemokine, and the surface expression of the immunosuppressive programmed death ligands 1 and 2. Higher concentrations of AZD1480 (5 μ) induced G2/M arrest and cell death by inhibiting Aurora kinases. Our study demonstrates that AZD1480 regulates proliferation and immunity in HL cell lines and provides mechanistic rationale for evaluating AZD1480 alone or in combination with MEK inhibitors in HL
Tanshinones Inhibit the Growth of Breast Cancer Cells through Epigenetic Modification of Aurora A Expression and Function
The objectives of this study were to evaluate the effects of tanshinones from a Chinese herb Salvia Miltiorrhiza on the growth of breast cancer cells, and to elucidate cellular and molecular mechanisms of action. Tanshinones showed the dose-dependent effect on the growth inhibition of breast cancer cells in vitro, with tanshinone I (T1) the most potent agent. T1 was also the only tanshinone to have potent activity in inhibiting the growth of the triple-negative breast cancer cell line MDA-MB231. T1 caused cell cycle arrests of both estrogen-dependent and estrogen-independent cell lines associated with alterations of cyclinD, CDK4 and cyclinB, and induced breast cancer cell apoptosis associated with upregulation of c-PARP and downregulation of survivin and Aurora A. Among these associated biomarkers, Aurora A showed the most consistent pattern with the anti-growth activity of tanshinones. Overexpression of Aurora A was also verified in breast tumors. The gene function assay showed that knockdown of Aurora A by siRNA dramatically reduced the growth-inhibition and apoptosis-induction activities of T1, suggesting Aurora A as an important functional target of T1 action. On the other hand, tanshinones had much less adverse effects on normal mammary epithelial cells. Epigenetic mechanism studies showed that overexpression of Aurora A gene in breast cancer cells was not regulated by gene promoter DNA methylation, but by histone acetylation. T1 treatment significantly reduced acetylation levels of histone H3 associated with Aurora A gene. Our results supported the potent activity of T1 in inhibiting the growth of breast cancer cells in vitro in part by downregulation of Aurora A gene function. Our previous studies also demonstrated that T1 had potent anti-angiogenesis activity and minimal side effects in vivo. Altogether, this study warrants further investigation to develop T1 as an effective and safe agent for the therapy and prevention of breast cancer
Hydraulic Method of Controlling Solids Retention Time in Step-Feed Biological Nitrogen Removal Process
- …