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1.  Mice Deficient in Sfrp1 Exhibit Increased Adiposity, Dysregulated Glucose Metabolism, and Enhanced Macrophage Infiltration 
PLoS ONE  2013;8(12):e78320.
The molecular mechanisms involved in the development of obesity and related complications remain unclear. Wnt signaling plays an important role in preadipocyte differentiation and adipogenesis. The expression of a Wnt antagonist, secreted frizzled related protein 1 (SFRP1), is increased in response to initial weight gain, then levels are reduced under conditions of extreme obesity in both humans and animals. Here we report that loss of Sfrp1 exacerbates weight gain, glucose homeostasis and inflammation in mice in response to diet induced obesity (DIO). Sfrp1-/- mice fed a high fat diet (HFD) exhibited an increase in body mass accompanied by increases in body fat percentage, visceral white adipose tissue (WAT) mass, and adipocyte size. Moreover, Sfrp1 deficiency increases the mRNA levels of key de novo lipid synthesis genes (Fasn, Acaca, Acly, Elovl, Scd1) and the transcription factors that regulate their expression (Lxr-α, Srebp1, Chreb, and Nr1h3) in WAT. Fasting glucose levels are elevated, glucose clearance is impaired, hepatic gluconeogenesis regulators are aberrantly upregulated (G6pc and Pck1), and glucose transporters are repressed (Slc2a2 and Slc2a4) in Sfrp1-/- mice fed a HFD. Additionally, we observed increased steatosis in the livers of Sfrp1-/- mice. When there is an expansion of adipose tissue there is a sustained inflammatory response accompanied by adipokine dysregulation, which leads to chronic subclinical inflammation. Thus, we assessed the inflammatory state of different tissues and revealed that Sfrp1-/- mice fed a HFD exhibited increased macrophage infiltration and expression of pro-inflammatory markers including IL-6, Nmnat, Tgf-β2, and SerpinE1. Our findings demonstrate that the expression of Sfrp1 is a critical factor required for maintaining appropriate cellular signaling in response to the onset of obesity.
PMCID: PMC3855156  PMID: 24339864
2.  Low-sodium diet self-management intervention in heart failure: pilot study results 
Self-care management of a low-sodium diet is a critical component of comprehensive heart failure (HF) treatment.
The primary purpose of this study was to examine the effectiveness of an educational intervention on reducing the dietary sodium intake of patients with HF. Secondary purposes were to examine the effects of the intervention on attitudes, subjective norm, and perceived behavioural control towards following a low-sodium diet.
This was a randomized clinical trial of an educational intervention based on The Theory of Planned Behavior. Patients were randomized to either a usual care (n=25) or intervention group (n=27) with data collection at baseline, 6 weeks, and 6 months. The intervention group received low-sodium diet instructions and the usual care group received no dietary instructions. Nutrition Data Systems-Research software was used to identify the sodium content of foods on food diaries. Attitudes, subjective norm, and perceived behavioural control were measured using the Dietary Sodium Restriction Questionnaire.
Analysis of covariance (between-subjects effects) revealed that dietary sodium intake did not differ between usual care and intervention groups at 6 weeks; however, dietary sodium intake was lower in the intervention group (F=7.3, df=1,29, p=0.01) at 6 months. Attitudes subscale scores were higher in the intervention group at 6 weeks (F=7.6, df=1, 38, p<0.01).
Carefully designed educational programmes have the potential to produce desired patient outcomes such as low-sodium diet adherence in patients with heart failure.
PMCID: PMC3811065  PMID: 22492785
Adherence; education; heart failure; low-sodium diet
3.  Transdifferentiation of glioblastoma stem-like cells into mural cells drives vasculogenic mimicry in glioblastomas 
Recent evidence has shown that glioblastoma stem-like cells (GSCs) can transdifferentiate into endothelial cells and vascular-like tumor cells. The latter pattern of vascularization indicates an alternative microvascular circulation known as vasculogenic mimicry (VM). However, it remains to be clarified how the GSC-driven VM makes a significant contribution to tumor vasculature. Here, we investigated eleven cases of glioblastomas and found that most of them consisted of blood-perfused vascular channels that co-express mural cell markers smooth muscle alpha actin and platelet-derived growth factor receptor β, epidermal growth factor receptor, and vascular endothelial growth factor receptor 2 (Flk-1), but not CD31 or VE-cadherin. This microvasculature co-existed with endothelial cell-associated vessels. GSCs derived from patients with glioblastomas developed vigorous mural cell-associated vascular channels but few endothelial cell vessels in orthotopic animal models. Suppression of Flk-1 activity and gene expression abrogated GSC transdifferentiation and vascularization in vitro, and inhibited VM in animal models. This study establishes mural-like tumor cells differentiated from GSCs as a significant contributor to microvasculature of glioblastoma and points to Flk-1 as a potential target for therapeutic intervention which could complement current anti-angiogenic treatment.
PMCID: PMC3461581  PMID: 22973019
vasculogenic mimicry; mural-like cell transdifferentiation; endothelial cell-transdifferentiation; glioblastoma stem-like cells
Acheron (Achn) is a new member of the Lupus Antigen family of RNA binding proteins. Previous studies have shown that Achn controls developmental decisions in neurons and muscle. In the human mammary gland, Achn expression is restricted to ductal myoepithelial cells. Microarray analysis and immunohistochemistry have shown that Achn expression is elevated in some basal-like ductal carcinomas. To study the possible role of Achn in breast cancer, we engineered human MDA-MB-231 cells to stably express enhanced green fluorescent protein-tagged wild-type Achn (AchnWT), as well as Achn lacking either its nuclear localization signal (AchnNLS) or its nuclear export signal (AchnNES). In in vitro assays, AchnWT and AchnNES, but not AchnNLS, enhanced cell proliferation, lamellipodia formation, and invasive activity and drove expression of the elevated expression of the metastasis-associated proteins MMP-9 and VEGF. To determine if Achn could alter the behavior of human breast cancer cells in vivo, Achn-engineered MDA-MB-231 cells were injected into athymic SCID/Beige mice. AchnWT and AchnNES-expressing tumors displayed enhanced angiogenesis and an approximately five-fold increase in tumor size relative to either control cells or those expressing AchnNLS. These data suggest that Achn enhances human breast tumor growth and vascularization, and that this activity is dependent on nuclear localization.
PMCID: PMC3388741  PMID: 21387291
invasion; metastasis; VEGF; MDA-MB-231 cells; xenograft; MMP9
5.  A YKL-40 neutralizing antibody blocks tumor angiogenesis and progression: a potential therapeutic agent in cancers 
Molecular cancer therapeutics  2011;10(5):742-751.
Accumulating evidence has indicated that expression levels of YKL-40, a secreted glycoprotein, were elevated in multiple advanced human cancers. Recently, we have identified an angiogenic role of YKL-40 in cancer development. However, blockade of the function of YKL-40, which implicates therapeutic value, has not been explored yet. Our current study sought to establish a monoclonal anti-YKL-40 antibody as a neutralizing antibody for the purpose of blocking tumor angiogenesis and metastasis. A mouse monoclonal anti-YKL-40 antibody (mAY) exhibited specific binding with recombinant YKL-40 and with YKL-40 secreted from osteoblastoma cells MG-63 and brain tumor cells U87. In the functional analysis, we found that mAY inhibited tube formation of microvascular endothelial cells in Matrigel induced by conditioned medium of MG-63 and U87 cells, as well as recombinant YKL-40. mAY also abolished YKL-40-induced activation of membrane receptor VEGF receptor 2 (Flk-1/KDR) and intracellular signaling MAP kinase Erk 1 and Erk 2. In addition, mAY enhanced cell death response of U87 line to γ-irradiation through decreased expression of pAKT and AKT, and accordingly abrogated angiogenesis induced by the conditioned medium of U87 cells in which YKL-40 levels were elevated by treatment with γ-irradiation. Furthermore, treatment of xenografted tumor mice with mAY restrained tumor growth, angiogenesis, and progression. Taken together, this study has demonstrated the therapeutic utility for the mAY in treatment of tumor angiogenesis and metastasis.
PMCID: PMC3091949  PMID: 21357475
YKL-40; a neutralizing antibody; tumor angiogenesis; tumor metastasis; γ-irradiation; signaling pathways
6.  In tumors Salmonella migrate away from vasculature toward the transition zone and induce apoptosis 
Cancer gene therapy  2011;18(7):457-466.
Motile bacteria can overcome diffusion resistances that substantially reduce the efficacy of standard cancer therapies. Many reports have also recently described the ability of Salmonella to deliver therapeutic molecules to tumors. Despite this potential, little is known about the spatiotemporal dynamics of bacterial accumulation in solid tumors. Ultimately this timing will affect how these microbes are used therapeutically. To determine how bacteria localize, we intravenously injected Salmonella typhimurium into BALB/c mice with 4T1 mammary carcinoma and measured the average bacterial content as a function of time. Immunohistochemistry was used to measure the extent of apoptosis; the average distance of bacteria from tumor vasculature; and the location of bacteria in four different regions: the core, transition, body and edge. Bacteria accumulation was also measured in pulmonary and hepatic metastases. The doubling time of bacterial colonies in tumors was measured to be 16.8 hours, and colonization was determined to delay tumor growth by 48 hours. From 12 and 48 hours after injection, the average distance between bacterial colonies and functional vasculature significantly increased from 130 to 310μm. After 48 hours, bacteria migrated away from the tumor edge toward the central core and induced apoptosis. After 96 hours, bacteria began to marginate to the tumor transition zone. All observed metastases contained Salmonella and the extent of bacterial co-localization with metastatic tissue was 44% compared to 0.5% with normal liver parenchyma. These results demonstrate that Salmonella can penetrate tumor tissue and can selectively target metastases, two critical characteristics of a targeted cancer therapeutic.
PMCID: PMC3117926  PMID: 21436868
Bacteriolytic Therapy; Attenuated Salmonella typhimurium; Tumor Transition Zone; Apoptosis; Metastases
7.  Inhibitory Activity of YKL-40 in Mammary Epithelial Cell Differentiation and Polarization Induced by Lactogenic Hormones: A Role in Mammary Tissue Involution 
PLoS ONE  2011;6(10):e25819.
We previously reported that a secreted glycoprotein YKL-40 acts as an angiogenic factor to promote breast cancer angiogenesis. However, its functional role in normal mammary gland development is poorly understood. Here we investigated its biophysiological activity in mammary epithelial development and mammary tissue morphogenesis. YKL-40 was expressed exclusively by ductal epithelial cells of parous and non-parous mammary tissue, but was dramatically up-regulated at the beginning of involution. To mimic ductal development and explore activity of elevated YKL-40 during mammary tissue regression in vivo, we grew a mammary epithelial cell line 76N MECs in a 3-D Matrigel system in the presence of lactogenic hormones including prolactin, hydrocortisone, and insulin. Treatment of 76N MECs with recombinant YKL-40 significantly inhibited acinar formation, luminal polarization, and secretion. YKL-40 also suppressed expression of E-cadherin but increased MMP-9 and cell motility, the crucial mechanisms that mediate mammary tissue remodeling during involution. In addition, engineering of 76N MECs with YKL-40 gene to express ectopic YKL-40 recapitulated the same activities as recombinant YKL-40 in the inhibition of cell differentiation. These results suggest that YKL-40-mediated inhibition of cell differentiation and polarization in the presence of lactogenic hormones may represent its important function during mammary tissue involution. Identification of this biophysiological property will enhance our understanding of its pathologic role in the later stage of breast cancer that is developed from poorly differentiated and highly invasive cells.
PMCID: PMC3185048  PMID: 21991364
8.  Theory-based Low-Sodium Diet Education for Heart Failure Patients 
Home healthcare nurse  2010;28(7):432-443.
Theory-based teaching strategies for promoting adherence to a low-sodium diet among patients with heart failure are presented in this manuscript. The strategies, which are based on the theory of planned behavior, address patient attitude, subjective norm, and perceived control as they learn how to follow a low-sodium diet. Home health clinicians can select a variety of the instructional techniques presented to meet individual patient learning needs.
PMCID: PMC2923425  PMID: 20592543
9.  Expression of human amyloid precursor protein in the skeletal muscles of Drosophila results in age- and activity-dependent muscle weakness 
BMC Physiology  2011;11:7.
One of the hallmarks of Alzheimer's disease, and several other degenerative disorders such as Inclusion Body Myositis, is the abnormal accumulation of amyloid precursor protein (APP) and its proteolytic amyloid peptides. To better understand the pathological consequences of inappropriate APP expression on developing tissues, we generated transgenic flies that express wild-type human APP in the skeletal muscles, and then performed anatomical, electrophysiological, and behavioral analysis of the adults.
We observed that neither muscle development nor animal longevity was compromised in these transgenic animals. However, human APP expressing adults developed age-dependent defects in both climbing and flying. We could advance or retard the onset of symptoms by rearing animals in vials with different surface properties, suggesting that human APP expression-mediated behavioral defects are influenced by muscle activity. Muscles from transgenic animals did not display protein aggregates or structural abnormalities at the light or transmission electron microscopic levels. In agreement with genetic studies performed with developing mammalian myoblasts, we observed that co-expression of the ubiquitin E3 ligase Parkin could ameliorate human APP-induced defects.
These data suggest that: 1) ectopic expression of human APP in fruit flies leads to age- and activity-dependent behavioral defects without overt changes to muscle development or structure; 2) environmental influences can greatly alter the phenotypic consequences of human APP toxicity; and 3) genetic modifiers of APP-induced pathology can be identified and analyzed in this model.
PMCID: PMC3112101  PMID: 21518451
amyloid precursor protein (APP); Drosophila; muscle; mitochondria; electron microscopy; apoptosis; Parkin
10.  YKL-40, a secreted glycoprotein, promotes tumor angiogenesis 
Oncogene  2009;28(50):4456-4468.
Tumor angiogenesis is of paramount importance in solid tumor development. Elevated serum levels of YKL-40, a secreted heparin-binding glycoprotein have been associated with a worse prognosis from a variety of advanced human cancers. Yet the role of YKL-40 activity in these cancers is still missing. Here, we have shown that ectopic expression of YKL-40 in MDA-MB-231 breast cancer cells and HCT-116 colon cancer cells led to larger tumor formation with an extensive angiogenic phenotype than did control cancer cells in mice. Affinity purified recombinant YKL-40 protein promoted vascular endothelial cell angiogenesis in vitro, the effects similar to the activities observed using MDA-MB-231 and HCT-116 cell conditioned medium after transfection with YKL-40. Further, YKL-40 was found to induce the coordination of membrane-bound receptor syndecan-1 and integrin αvβ3 and activate an intracellular signaling cascade including focal adhesion kinase and MAP kinase Erk1/2 in endothelial cells. Also, blockade of YKL-40 using siRNA gene knockdown suppressed tumor angiogenesis in vitro and in vivo. Immunohistochemical analysis of human breast cancer revealed a correlation between YKL-40 expression and blood vessel density. These findings provide novel insights into angiogenic activities and molecular mechanisms of YKL-40 in cancer development.
PMCID: PMC2795793  PMID: 19767768
11.  Gender differences in adherence to the sodium-restricted diet in patients with heart failure 
Journal of cardiac failure  2006;12(8):628.
Despite the importance of the sodium restricted diet (SRD) to heart failure (HF) management, patient adherence is poor. Little is known about gender differences in adherence or factors that affect patients’ ability to follow SRD recommendations. The purposes of this study were to determine whether there were gender differences in (1) adherence to the SRD; (2) knowledge about SRD and HF self-care; and (3) perceived barriers to following the SRD.
Methods and Results
Forty-one men and twenty-seven women completed the Heart Failure Attitudes and Barriers questionnaire that measured HF self-care, knowledge and perceived barriers to following a SRD. Diet adherence was measured by 24-hour urinary sodium excretion (UNa). Women were more adherent to the SRD than men as reflected by 24-hour urine excretion (2713 vs. 3859 mg UNa, p=.01). Women recognized signs of excess sodium intake such as fluid build-up (p=.001) and edema (p=.01) more often than men and had better understanding of appropriate actions to take related to following a SRD. There were no gender differences in perceived barriers to following a SRD.
Although men and women perceived similar barriers, women were more adherent to the SRD and had greater knowledge about following a SRD. Further investigation of this phenomenon is warranted to determine if better adherence contributes to improved outcomes in women.
PMCID: PMC2821740  PMID: 17045182
Women; Knowledge; Barrier
12.  Distinct Angiogenic Mediators Are Required for Basic Fibroblast Growth Factor– and Vascular Endothelial Growth Factor–induced Angiogenesis: The Role of Cytoplasmic Tyrosine Kinase c-Abl in Tumor Angiogenesis 
Molecular Biology of the Cell  2008;19(5):2278-2288.
Signaling pathways engaged by angiogenic factors bFGF and VEGF in tumor angiogenesis are not fully understood. The current study identifies cytoplasmic tyrosine kinase c-Abl as a key factor differentially mediating bFGF- and VEGF-induced angiogenesis in microvascular endothelial cells. STI571, a c-Abl kinase inhibitor, only inhibited bFGF- but not VEGF-induced angiogenesis. bFGF induced membrane receptor cooperation between integrin β3 and FGF receptor, and triggered a downstream cascade including FAK, c-Abl, and MAPK. This signaling pathway is different from one utilized by VEGF that includes integrin β5, VEGF receptor-2, Src, FAK, and MAPK. Ectopic expression of wild-type c-Abl sensitized angiogenic response to bFGF, but kinase dead mutant c-Abl abolished this activity. Furthermore, the wild-type c-Abl enhanced angiogenesis in both Matrigel implantation and tumor xenograft models. These data provide novel insights into c-Abl's differential functions in mediating bFGF- and VEGF-induced angiogenesis.
PMCID: PMC2366879  PMID: 18353972

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