Crossveinless 2 regulates bone morphogenetic protein 9 in human and mouse vascular endothelium

The importance of morphogenetic proteins (BMPs) and their antagonists in vascular development is increasingly being recognized. BMP-4 is essential for angiogenesis and is antagonized by matrix Gla protein (MGP) and crossveinless 2 (CV2), both induced by the activin receptor like-kinase 1 (ALK1) when stimulated by BMP-9. In this study, however, we show that CV2 preferentially binds and inhibits BMP-9 thereby providing strong feedback inhibition for BMP-9/ALK1 signaling rather than for BMP-4/ALK2 signaling. CV2 disrupts complex formation involving ALK2, ALK1, BMP-4, and BMP-9 required for the induction of both BMP antagonists. It also limits VEGF expression, proliferation, and tube formation in ALK1-expressing endothelial cells. In vivo, CV2 deficiency translates into a dysregulation of vascular BMP signaling, resulting in an abnormal endothelium with increased endothelial cellularity and expression of lineage markers for mature endothelial cells. Thus, mutual regulation by BMP-9 and CV2 is essential in regulating the development of the vascular endothelium.     

An investigation of antidiabetic activities of bioactive compounds in Euphorbia hirta Linn using molecular docking and pharmacophore

Herbal remedies have been considered as potential medication for diabetes type 2 treatment. Bitter melons, onions, or Goryeong Ginsengs are popular herbals and their functions in diabetes patients have been well documented. Recently, the Euphorbia hirta has been shown to have strong effects on diabetes in mice, however, there has been no research clearly indicating what the active compound is. The main purpose of the current study was therefore to evaluate whether a relationship exists between various bioactive compounds in E. hirta Linn and targeted protein relating diabetes type 2 in human. In view of this, extraction from E. hirta Linn was tested if they contained the bioactive compounds. This process involved the docking of 3D structures of those substances (ligand) into targeted proteins: 11-β hydroxysteroid dehydrogenase type 1, glutamine: fructose-6-phosphate amidotransferase, protein phosphatase, and mono-ADP-ribosyltransferase sirtuin-6. Then, LigandScout was applied to evaluate the bond formed between ligand and the binding pocket in the protein. These test identified in eight substances with high binding affinity (<?8.0 kcal/mol) to all four interested proteins of this article. The substances are quercetrin, rutin, myricitrin, cyanidin 3,5-O-diglucoside, pelargonium 3,5-diglucose in “flavonoid family” and α-amyrine, β-amyrine, taraxerol in “terpenes group.” The result can be explained by the 2D picture which showed hydrophobic interaction, hydrogen bond acceptor, and hydrogen bond donor forming between carbonyl oxygen molecules of ligand with free residues in the protein. These pictures of the bonding provide evidence that E. hirta Linn may prove to be an effective treatment for diabetes type 2.     

Diagnosing Rhodococcus equi Infections in a Setting Where Tuberculosis Is Highly Endemic: a Double Challenge

Rhodococcus equi infection is increasing in regions with high HIV prevalence worldwide. The microbiological features and clinical mimicry of tuberculosis infection pose diagnostic challenges in high-tuberculosis-incidence settings. We present two HIV-associated cases of R. equi infection from Vietnam and discuss the unique diagnostic challenges in such settings.     

Musashi2 sustains the mixed-lineage leukemia–driven stem cell regulatory program

Leukemia stem cells (LSCs) are found in most aggressive myeloid diseases and contribute to therapeutic resistance. Leukemia cells exhibit a dysregulated developmental program as the result of genetic and epigenetic alterations. Overexpression of the RNA-binding protein Musashi2 (MSI2) has been previously shown to predict poor survival in leukemia. Here, we demonstrated that conditional deletion of Msi2 in the hematopoietic compartment results in delayed leukemogenesis, reduced disease burden, and a loss of LSC function in a murine leukemia model. Gene expression profiling of these Msi2-deficient animals revealed a loss of the hematopoietic/leukemic stem cell self-renewal program and an increase in the differentiation program. In acute myeloid leukemia patients, the presence of a gene signature that was similar to that observed in Msi2-deficent murine LSCs correlated with improved survival. We determined that MSI2 directly maintains the mixed-lineage leukemia (MLL) self-renewal program by interacting with and retaining efficient translation of Hoxa9, Myc, and Ikzf2 mRNAs. Moreover, depletion of MLL target Ikzf2 in LSCs reduced colony formation, decreased proliferation, and increased apoptosis. Our data provide evidence that MSI2 controls efficient translation of the oncogenic LSC self-renewal program and suggest MSI2 as a potential therapeutic target for myeloid leukemia.     

NB4细胞株分化中NDRG1表达的研究

目的:应用多种分化诱导剂处理急性早幼粒细胞白血病(APL)细胞系NB4细胞株,探讨NDRG1表达在白血病细胞诱导分化中的作用.方法:采用1×10-7mol/L全反式维甲酸(ATRA)、1%二甲基亚砜(DMSO)和20nmol/L佛波酯(TPA)分别处理NB4细胞48h,并通过细胞染色、流式细胞检测、蛋白印迹(Western blot)和实时PCR分别检测分化细胞的核型、CDllb、CDllc、CDl4表达,观察ndrgl mRNA与蛋白的变化.结果:3种分化诱导剂分别处理细胞株后,细胞核缩小且呈分叶状改变,细胞内NDRG1蛋白表达均呈时间依赖性上调;经ATRA和DMSO处理的细胞,其ndrgl mRNA发生上调,而经TPA处理的细胞却未发生ndrgl mRNA表达上调.结论:细胞信号调控分子NDRG1与细胞分化密切相关.