A5005730255- Metabolism, Diabetes, and Cancer
- Angiogenesis and VEGF in Cancer
- Atherosclerosis and Cardiovascular Diseases
- Ubiquitin and proteasome pathways
- Cancer, Hypoxia, and Metabolism
- Pancreatic function and diabetes
- Cell Adhesion Molecules Research
- Protease and Inhibitor Mechanisms
- Glycosylation and Glycoproteins Research
- Plant tissue culture and regeneration
- Autophagy in Disease and Therapy
- Cancer, Lipids, and Metabolism
- Phagocytosis and Immune Regulation
- Alzheimer's disease research and treatments
- Endoplasmic Reticulum Stress and Disease
- Cholesterol and Lipid Metabolism
- Cellular transport and secretion
- Calpain Protease Function and Regulation
- S100 Proteins and Annexins
- Single-cell and spatial transcriptomics
- Adipose Tissue and Metabolism
- ATP Synthase and ATPases Research
- Hormonal Regulation and Hypertension
- Kruppel-like factors research
- Galectins and Cancer Biology
Sichuan University
2022-2025
Harvard University
2016-2024
Boston Children's Hospital
2016-2024
Boston Children's Museum
2016-2023
Chengdu Fifth People's Hospital
2022
State Key Laboratory of Biotherapy
2022
Oklahoma Medical Research Foundation
2012-2018
Family Research Institute
2016-2017
Yuncheng University
2016-2017
University of Tennessee at Knoxville
2003-2017
Autophagy is a critical cellular system for removal of aggregated proteins and damaged organelles. Although dysregulated autophagy implicated in the development heart failure, role diabetic cardiomyopathy has not been studied. We investigated whether chronic activation AMP-activated protein kinase (AMPK) by metformin restores cardiac function cardiomyocyte OVE26 mice.OVE26 mice cardiac-specific AMPK dominant negative transgenic (DN)-AMPK were treated with or vehicle 4 months, autophagy,...
Background— Aberrant endoplasmic reticulum (ER) stress is associated with several cardiovascular diseases, including atherosclerosis. The mechanism by which aberrant ER develops poorly understood. This study investigated whether dysfunction of AMP-activated protein kinase (AMPK) causes and atherosclerosis in vivo. Methods Results— Human umbilical vein endothelial cells mouse aortic from AMPK-deficient mice were used to assess the level Western blotting. Reduction AMPKα2 expression...
Background— Metformin, one of most commonly used antidiabetes drugs, is reported to exert its therapeutic effects by activating AMP-activated protein kinase (AMPK); however, the mechanism which metformin activates AMPK poorly defined. The objective present study was determine how in endothelial cells. Methods and Results— Exposure human umbilical vein cells or bovine aortic significantly increased activity phosphorylation both at Thr172 LKB1 Ser428, an kinase, paralleled activation C...
OBJECTIVE The oxidation of LDLs is considered a key step in the development atherosclerosis. How LDL contributes to atherosclerosis remains poorly defined. Here we report that oxidized and glycated (HOG-LDL) causes aberrant endoplasmic reticulum (ER) stress AMP-activated protein kinase (AMPK) suppressed HOG-LDL–triggered ER vivo. RESEARCH DESIGN AND METHODS markers, sarcoplasmic/endoplasmic Ca2+ ATPase (SERCA) activity oxidation, AMPK were monitored cultured bovine aortic endothelial cells...
We previously reported the phosphoinositide 3-kinase-dependent activation of 5′-AMP-activated kinase (AMPK) by peroxynitrite (ONOO-) and hypoxia-reoxygenation in cultured endothelial cells. Here we show molecular mechanism this pathway. Exposure bovine aortic cells to ONOO- significantly increased phosphorylation both Thr172 AMPK Ser1179 nitric-oxide synthase, a known downstream enzyme AMPK. In addition, was accompanied protein Cζ (PKCζ) (Thr410/403) translocation cytosolic PKCζ into...
Background— Oxidative stress plays a causal role in vascular injury diabetes mellitus, but the mechanisms and targets remain poorly understood. Methods Results— Exposure of cultured human umbilical vein endothelial cells to either peroxynitrite (ONOO − ) or high glucose significantly inhibited both basal insulin-stimulated Akt phosphorylation at Ser473 activity parallel with increased apoptosis, phosphorylation, phosphatase tensin homologue deleted on chromosome 10 (PTEN). Furthermore,...
Epsins are a family of ubiquitin-binding, endocytic clathrin adaptors. Mice lacking both epsins 1 and 2 (Epn1/2) die at embryonic day 10 exhibit an abnormal vascular phenotype. To examine the angiogenic role endothelial epsins, we generated mice with constitutive or inducible deletion Epn1/2 in endothelium. These exhibited no phenotypes under normal conditions, suggesting that lack did not affect blood vessels. In tumors, however, loss resulted disorganized vasculature, significantly...
Epsin endocytic adaptor proteins are implicated in the progression of atherosclerosis; however, underlying molecular mechanisms have not yet been fully defined. In this study, we determined how epsins enhance endothelial-to-mesenchymal transition (EndoMT) atherosclerosis and assessed efficacy a therapeutic peptide preclinical model disease.
Chronic kidney disease (CKD) ultimately causes renal fibrosis and end-stage disease, thus seriously threatens human health. However, current medications for CKD are inefficient, which is often due to poor targeting capability tubule. In this study, we discover that biomimetic high-density lipoprotein (bHDL) lipid nanoparticles possess excellent ability injured tubular epithelial cells by injury molecule-1(KIM-1) mediated internalization. Thus, co-load anti-inflammatory drug triptolide (TP)...
Gamma-secretase cleavage of beta-amyloid precursor protein (APP) is crucial in the pathogenesis Alzheimer disease, because it decisive step formation C terminus (Abeta). To better understand molecular events involved gamma-secretase APP, this study we report identification a new intracellular long Abeta species containing residues 1-46 (Abeta46), which led to novel zeta-cleavage site between known gamma- and epsilon-cleavage sites within transmembrane domain APP. Our data clearly demonstrate...
beta-Amyloid precursor protein apparently undergoes at least three major cleavages, gamma-, epsilon-, and the newly identified zeta-cleavage, within its transmembrane domain to produce secreted beta-amyloid (Abeta). However, roles of epsilon- zeta-cleavages in formation Abeta relationship among these namely zeta-, gamma-cleavages, remain elusive. We investigated issues by attempting determine turnover intermediate products generated presence or absence known gamma-secretase inhibitors. By...
In endothelial cells, the AMP-activated protein kinase (AMPK) is stimulated by sheer stress or growth factors that stimulate release of nitric oxide (NO). We hypothesized NO might act as an endogenous activator AMPK in cells. Exposure human umbilical vein cells (HUVECs) to donors caused increase phosphorylation both Thr-172 and Ser-1177 synthase, a downstream enzyme AMPK. NO-induced activation was not affected inhibition LKB1, kinase. contrast, calcium calmodulin-dependent abolished effect...
LKB1, a master kinase that controls at least 13 downstream protein kinases including the AMP-activated (AMPK), resides mainly in nucleus. A key step LKB1 activation is its export from nucleus to cytoplasm. Here, we identified S307 of as putative novel phosphorylation site which essential for nucleocytoplasmic transport. In cell-free system, recombinant PKC-zeta phosphorylates S307. AMPK-activating agents stimulate activity and endothelial cells, hepatocytes, skeletal muscle vascular smooth...
Excess cholesterol accumulation in lesional macrophages elicits complex responses atherosclerosis. Epsins, a family of endocytic adaptors, fuel the progression atherosclerosis; however, underlying mechanism and therapeutic potential targeting Epsins remains unknown. In this study, we determined role macrophage-mediated metabolic regulation. We then developed an innovative method to therapeutically target macrophage with specially designed S2P-conjugated lipid nanoparticles, which encapsulate...
The AMP-activated protein kinase (AMPK) is reported to mediate the beneficial effects of statin on vascular functions, but biochemical mechanisms are incompletely understood. aim study was determine how activates AMPK. Exposure confluent bovine aortic endothelial cells simvastatin (statin) dose-dependently increased phosphorylation AMPK at Thr172 and activities AMPK, which in parallel with detection both LKB1 Ser428 nuclear export. Furthermore, treatment shown increase C (PKC)-ζ activity...
Thromboxane A 2 receptor (TPr) stimulation induces cellular hypertrophy in vascular smooth muscle cells (VSMCs); however, regulation of VSMC remains poorly understood. Here we show that TPr activates AMP-activated kinase (AMPK), which turn limits TPr-induced protein synthesis VSMCs. Exposure cultured VSMCs to either agonists, IBOP and U46619, or exogenous hydrogen peroxide (H O ) caused time- dose-dependent AMPK activation, as evidenced by increased phosphorylation both AMPK-Thr172...
Atherosclerosis is, in part, caused by immune and inflammatory cell infiltration into the vascular wall, leading to enhanced inflammation lipid accumulation aortic endothelium. Understanding molecular mechanisms underlying this disease is critical for development of new therapies. Our recent studies demonstrate that epsins, a family ubiquitin-binding endocytic adaptors, are regulators atherogenicity. Given fundamental contribution lesion macrophages make fuel atherosclerosis, whether how...
Impaired lymphangiogenesis is a complication of chronic complex diseases, including diabetes. VEGF-C/VEGFR3 signaling promotes lymphangiogenesis, but how this pathway affected in diabetes remains poorly understood. We previously demonstrated that loss epsins 1 and 2 lymphatic endothelial cells (LECs) prevented VEGF-C–induced VEGFR3 from endocytosis degradation. Here, we report attenuated corneal micropocket Matrigel plug assays WT mice not with inducible lymphatic-specific deficiency...
LKB1 is a serine-threonine protein kinase that, when inhibited, may result in unregulated cell growth and tumor formation. However, how regulated remains poorly understood. The aim of the present study was to define upstream signaling events responsible for peroxynitrite (ONOO(-))-induced activation. Exposure cultured human umbilical vein endothelial cells low concentration ONOO(-) (5 microM) significantly increased phosphorylation at Ser(428) Czeta (PKCzeta) Thr(410). These effects were...
We previously showed that endothelial epsin deficiency caused elevated vascular growth factor receptor 2 (VEGFR2) and enhanced VEGF signaling, resulting in aberrant tumor angiogenesis reduced adult mice. However, direct evidence demonstrating epsins regulate specifically through VEGFR2 downregulation is still lacking. In addition, whether the lack of causes abnormal during embryonic development remains unclear.A novel strain epsin-deleted mice are heterozygous for (Epn1(fl/fl); Epn2(-/-);...