Discovery of a novel Nrf2 inhibitor that induces apoptosis of human acute myeloid leukemia cells.

Nuclear factor-erythroid 2-related factor 2 (Nrf2) is persistently activated in many human tumors including acute myeloid leukemia (AML). Therefore, inhibition of Nrf2 activity may be a promising target in leukemia therapy. Here, we used an antioxidant response element-luciferase reporter system to identify a novel pyrazolyl hydroxamic acid derivative, 1-(4-(tert-Butyl)benzyl)-3-(4-chlorophenyl)-N-hydroxy-1H pyrazole-5-carboxamide (4f), that inhibited Nrf2 activity.

Inhibition of ANXA7 GTPase activity by a small molecule promotes HMBOX1 translation of vascular endothelial cells in vitro and in vivo.

Homeobox containing 1 (HMBOX1) is essential for the survival of human umbilical vein endothelial cells (HUVECs). However, the regulatory mechanism of HMBOX1 expression is still unclear. We recently found that a small molecule 6-amino-2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine (ABO) directly targeted annexin A7 (ANXA7) and inhibited its GTPase activity.

A small molecule induces integrin β4 nuclear translocation and apoptosis selectively in cancer cells with high expression of integrin β4.

Increased integrin β4 (ITGB4) level is accompanied by malignant progression of multiple carcinomas. However, selective therapeutic strategies against cancer cells expressing a high level of ITGB4 have not been reported. Here, for the first time, we report that a chiral small molecule, SEC, selectively promotes apoptosis in cancer cells expressing a high level of ITGB4 by inducing ITGB4 nuclear translocation.

Identification of New Small Molecules as Apoptosis Inhibitors in Vascular Endothelial Cells.

Vascular endothelial cell (VEC) apoptosis is involved in the development of atherosclerosis and other cardiovascular diseases. We previously found that ethyl 1-(2-hydroxy-3-aroxypropyl)-3-aryl-1H-pyrazole -5-carboxylate derivatives (3a-o) play important roles in cell fate control. In this study, among the 15 compounds, we further screened 2 compounds, 3d and 3k, that suppressed VEC apoptosis induced by deprivation of serum and fibroblast growth factor 2.

A new microRNA signal pathway regulated by long noncoding RNA TGFB2-OT1 in autophagy and inflammation of vascular endothelial cells.

TGFB2-OT1 (TGFB2 overlapping transcript 1) is a newly discovered long noncoding RNA (lncRNA) derived from the 3'UTR of TGFB2. It can regulate autophagy in vascular endothelial cells (VECs). However, the mechanisms of TGFB2-OT1 action are unclear, and whether it is involved in VECs dysfunction needs investigation.

HMBOX1 interacts with MT2A to regulate autophagy and apoptosis in vascular endothelial cells.

We previously found that Homeobox containing 1 (HMBOX1) was required for bone mesenchymal stem cell (BMSC) and mouse embryonic stem cell (ESC) differentiation into vascular endothelial cells (VECs). However, the function of HMBOX1 in VECs is still unknown. In this study, we found that HMBOX1 was abundantly expressed in the cytoplasm of human umbilical vascular endothelial cells (HUVECs).

Nano-Mg(OH)2-induced proliferation inhibition and dysfunction of human umbilical vein vascular endothelial cells through caveolin-1-mediated endocytosis.

Nano-Mg(OH)2 is efficiently used in pollutant adsorption and removal due to its high adsorption capability, low-cost, and recyclability. A recent research from our group showed that Mg(OH)2 nanoflakes are not evidently internalized by cancer cells and are not cytotoxic. But the biocompatibility and potential toxicity of nano-Mg(OH)2 in a normal biological system are largely unclear.

A 3'UTR-associated RNA, FLJ11812 maintains stemness of human embryonic stem cells by targeting miR-4459.

The 3' untranslated region (UTR)-associated RNAs (uaRNAs) have important roles in various biological processes, especially in development. However, since they overlap with protein-coding mRNAs, uaRNAs are difficult to study by RNA interference techniques. We recently identified a chemical molecule, 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one (3BDO), that could efficiently induce human embryonic stem cells (hESCs) differentiation, and meanwhile selectively and efficiently downregulate the uaRNA FLJ11812.

An activator of mTOR inhibits oxLDL-induced autophagy and apoptosis in vascular endothelial cells and restricts atherosclerosis in apolipoprotein E⁻/⁻ mice.

Oxidized low-density lipoprotein (oxLDL) inhibits mammalian target of rapamycin (mTOR) and induces autophagy and apoptosis in vascular endothelial cells (VECs) that play very critical roles for the cardiovascular homostasis. We recently defined 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one (3BDO) as a new activator of mTOR. Therefore, we hypothesized that 3BDO had a protective role in VECs and thus stabilized atherosclerotic lesions in apolipoprotein E(-/-) (apoE(-/-)) mice.

Finding ATF4/p75NTR/IL-8 signal pathway in endothelial-mesenchymal transition by safrole oxide.

Targeting the endothelial-to-mesenchymal transition (EndoMT) may be a novel therapeutic strategy for cancer and various diseases induced by fibrosis. We aimed to identify a small chemical molecule as an inducer of EndoMT and find a new signal pathway by using the inducer. Safrole oxide (SFO), 50 µg/ml, could most effectively induce EndoMT within 12 h.

Identification of a novel MTOR activator and discovery of a competing endogenous RNA regulating autophagy in vascular endothelial cells.

MTOR, a central regulator of autophagy, is involved in cancer and cardiovascular and neurological diseases. Modulating the MTOR signaling balance could be of great significance for numerous diseases. No chemical activators of MTOR have been found, and the urgent challenge is to find novel MTOR downstream components.

ZnS nanoarchitectures induced dysfunction of vascular endothelial cells in vitro and in vivo.

ZnS nanoarchitectures have been intensively investigated recently because of their applications in optoelectronics and adsorption capacity. The potential hazard of ZnS nanoarchitectures is not well known. In this study, we investigated the toxicity of ZnS nanoarchitectures on vascular endothelial cell (VEC) in vitro and in vivo.

Phosphatidylethanolamine binding protein 1 in vacular endothelial cell autophagy and atherosclerosis.

We previously found that phosphatidylcholine-specific phospholipase C (PC-PLC) was a key inducing element of atherosclerosis, and might negatively regulate human umbilical vein endothelial cell (HUVEC) autophagy. To further investigate the mechanism of PC-PLC action, we initially identified phosphatidylethanolamine binding protein 1 (PEBP1) as a binding partner of PC-PLC by using mass spectrometry (MS, MALDI-TOF/TOF). We found that PEBP1 positively regulated PC-PLC activity in HUVECs, and inhibition of PC-PLC by its inhibitor D609 suppressed PEBP1 expression dramatically.

Novel ferrocenyl derivatives exert anti-cancer effect in human lung cancer cells in vitro via inducing G1-phase arrest and senescence.

Aim: To investigate the effects of 7 novel 1-ferrocenyl-2-(5-phenyl-1H-1,2,4-triazol-3-ylthio) ethanone derivatives on human lung cancer cells in vitro and to determine the mechanisms of action.

Methods: A549 human lung cancer cells were examined. Cell viability was analyzed with MTT assay.

The effect of novel magnetic nanoparticles on vascular endothelial cell function in vitro and in vivo.

Manufactured nanoparticles are currently used for many fields. However, their potential toxicity provides a growing concern for human health. In our previous study, we prepared novel magnetic nanoparticles (MNPs), which could effectively remove heavy metal ions and cationic dyes from aqueous solution.

Human vascular endothelial cells reduce sphingosylphosphorylcholine-induced smooth muscle cell contraction in co-culture system through integrin β4 and Fyn.

Aim: In vascular strips, the adjacent endothelial cells modulate the contraction of vascular smooth muscle cells (VSMCs) induced by sphingosylphosphorylcholine (SPC) through nitric oxide (NO). The aim of this study was to elucidate the mechanisms by which vascular endothelial cells (VECs) reduce the SPC-induced contraction of VSMCs in a co-culture system.

Methods: Human umbilical VECs and VSMCs were co-cultured.

Safrole oxide induces human umbilical vein endothelial cell transdifferentiation to 5-hydroxytryptaminergic neuron-like cells through tropomyosin receptor kinase A/cyclooxygenase 2/nuclear factor-kappa B/interleukin 8 signaling.

The phenomenon of endothelial-neural transdifferentiation has been observed for a long time, but the mechanism is not clear. We previously found that safrole oxide induced human umbilical vein endothelial cell transdifferentiation into neuron-like cells. In this study, we first validated that these cells induced by safrole oxide were functional 5-hydroxytryptaminergic neuron-like cells.

Microwave-assisted synthesis, crystal structure of pyrazolo[1,5-a]pyrazin-4(5H)-ones and their selective effects on lung cancer cells.

A series of novel pyrazolo[1,5-a]pyrazin-4(5H)-one derivatives with hydrophilic group was synthesized under general heating condition and microwave-assisted condition. The structures of compounds were determined by IR, 1H NMR and HRMS, moreover, representative crystal structures were characterized by using X-ray diffraction analysis. Preliminary biological evaluation showed that some compounds could inhibit the growth of A549, H322 and H1299 cells in dosage dependent manners.

Lipopolysaccharide activated phosphatidylcholine-specific phospholipase C and induced IL-8 and MCP-1 production in vascular endothelial cells.

Secretion of proinflammatory cytokines by lipopolysaccharide (LPS) activated vascular endothelial cells (VECs) contributes substantially to the pathogenesis of several inflammatory diseases such as atherosclerosis and septic shock. However, the mechanisms involved in this process are not well understood. Here, we investigated the role of phosphatidylcholine-specific phospholipase C (PC-PLC) in LPS-induced IL-8 and MCP-1 production in VECs.

N-benzyl-5-phenyl-1H-pyrazole-3-carboxamide promotes vascular endothelial cell angiogenesis and migration in the absence of serum and FGF-2.

Aim: To investigate the effect of N-benzyl-5-phenyl-1H-pyrazole-3-carboxamide (BPC) on angiogenesis in human umbilical vein endothelial cells (HUVECs).

Methods: Capillary-like tube formation on matrigel and cell migration analyses were performed in the absence of serum and fibroblast growth factor (FGF-2). Reactive oxygen species (ROS) were measured using a fluorescent probe, 2', 7'- dichlorodihydrofluorescein (DCHF).

Distinct patterns of autophagy evoked by two benzoxazine derivatives in vascular endothelial cells.

Macroautophagy (referred to as autophagy) is an evolutionarily conserved, bulk-destruction process in eukaryotes. During this process, the cytoplasm containing long-lived proteins and organelles is engulfed into double-membrane autophagosomes, and ultimately undergoes enzymatic degradation within lysosomes. Autophagy serves as a prosurvival machinery, or it may contribute to cell death.

Role of Hmbox1 in endothelial differentiation of bone-marrow stromal cells by a small molecule.

Bone marrow stromal cells (BMSCs) play critical roles in repairing endothelium damage. However, the mechanisms underlying BMSC differentiation into vascular endothelial cells (VECs) is not well understood. We aimed to find new factors involved in this process by exploiting a novel chemical inducer in a gene microarray assay.

Modulation of vascular endothelial cell senescence by integrin β4.

Increasing evidence has demonstrated that the senescence of vascular endothelial cells (VECs) has critical roles in the pathogenesis of vascular dysfunction. Finding important factors that regulate VEC senescence will help provide novel therapeutic strategies for vascular disorders. Previously, we found that integrin β4 was involved in VEC senescence.

Lipopolysaccharide induces autophagy through BIRC2 in human umbilical vein endothelial cells.

Lipopolysaccharide (LPS), as an important proinflammatory agent, targets the endothelium. However, almost all in vitro experiments of the effect of LPS on vascular endothelial cells (VECs) were performed under an artificially decreased concentration of serum that was not enough to maintain the cell growth for a long time. The mechanism underlying LPS action on VECs cultured in a nutrient-rich condition is not clear.

Discovery of a benzoxazine derivative promoting angiogenesis in vitro and in vivo.

Angiogenesis is a multi-step process that refers to the growth of new vessels from pre-existing ones. Endothelial proliferation, migration, and tube formation constitute a critical step in angiogenesis. Recently, we demonstrated that a novel benzoxazine derivative, 6-amino-2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine (ABO) could improve the proliferation of human umbilical vein endothelial cells (HUVECs) without basic fibroblast growth factor (bFGF) and serum.