Louisville Veterans Administration Medical Center

Louisville, KY, United States

Louisville Veterans Administration Medical Center

Louisville, KY, United States
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Ding C.,University of Louisville | Ma Y.,University of Louisville | Chen X.,University of Louisville | Chen X.,Nanjing Medical University | And 10 more authors.
Nature Communications | Year: 2013

A variant of the integrin-α-M (CD11b) gene has been linked to the pathogenesis of systemic lupus erythematosus. However, how this genotype results in the lupus phenotype is not fully understood. Here we show that autoreactive B cells lacking CD11b exhibit a hyperproliferative response to B cell receptor (BCR) crosslinking and enhanced survival. In vivo engagement of BCR in CD11b-deficient mice leads to increased autoAb production and kidney Ig deposition. In addition, CD11b-deficient autoreactive B cells have decreased tyrosine phosphorylation including Lyn and CD22 with decreased phosphatase SHP-1 recruitment but increased calcium influx. Results obtained using B cells transfected with the wild type or rs1143679 lupus-associated variant of CD11b suggest that this mutation completely abrogates the regulatory effect of CD11b on BCR signalling. This is through disruption of CD22-CD11b direct binding. These results reveal a previously unrecognized role of CD11b in maintaining autoreactive B cell tolerance. © 2013 Macmillan Publishers Limited. All rights reserved.


Zhuang X.,Yangzhou University | Zhuang X.,University of Louisville | Xiang X.,University of Louisville | Grizzle W.,University of Alabama at Birmingham | And 10 more authors.
Molecular Therapy | Year: 2011

In this study, exosomes used to encapsulate curcumin (Exo-cur) or a signal transducer and activator of transcription 3 (Stat3) inhibitor, i.e., JSI124 (Exo-JSI124) were delivered noninvasively to microglia cells via an intranasal route. The results generated from three inflammation-mediated disease models, i.e., a lipopolysaccharide (LPS)-induced brain inflammation model, experimental autoimmune encephalitis and a GL26 brain tumor model, showed that mice treated intranasally with Exo-cur or Exo-JSI124 are protected from LPS-induced brain inflammation, the progression of myelin oligodendrocyte glycoprotein (MOG) peptide induced experimental autoimmune encephalomyelitis (EAE), and had significantly delayed brain tumor growth in the GL26 tumor model. Intranasal administration of Exo-cur or Exo-JSI124 led to rapid delivery of exosome encapsulated drug to the brain that was selectively taken up by microglial cells, and subsequently induced apoptosis of microglial cells. Our results demonstrate that this strategy may provide a noninvasive and novel therapeutic approach for treating brain inflammatory-related diseases. © 2011 The American Society of Gene & Cell Therapy.


Liu Y.,University of Alabama at Birmingham | Xiang X.,University of Alabama at Birmingham | Xiang X.,University of Louisville | Zhuang X.,University of Alabama at Birmingham | And 9 more authors.
American Journal of Pathology | Year: 2010

In this study we observed that mice pretreated with tumor exosomes had a significant acceleration of tumor metastasis in the lung. Tumor metastasis correlated significantly with an increase in recruitment of more Myeloid-derived suppressor cells (MDSCs) in the lung of C57BL/6j (B6) mice pretreated with tumor exosomes. These effects were blunted when MyD88 knockout (KO) mice were pretreated with tumor exosomes. MDSCs induced by tumor exosomes and isolated from wild-type B6 mice also more potently inhibited T cell activation and induction of interleukin-6 and tumor necrosis factor-α than MDSCs isolated from the lung of MyD88 KO mice. In vitro, addition of tumor exosomes to bone marrow-derived CD11b+ Gr-1+ cells isolated from wild-type B6 mice resulted in more cytokine production, including tumor necrosis factor-α, interleukin-6, and the chemokine CCL2, than CD11b +Gr-1+ cells isolated from MyD88 KO mice. Moreover, lower levels of CCL2 were observed in the lungs in MyD88 KO mice pretreated with tumor exosomes than that in wild-type mice. Together these data demonstrate a pivotal role for MyD88 in tumor exosome-mediated expansion of MDSCs and tumor metastasis. Copyright © American Society for Investigative Pathology.


Xiang X.,University of Louisville | Zhuang X.,University of Louisville | Ju S.,University of Louisville | Zhang S.,University of Alabama at Birmingham | And 7 more authors.
Oncogene | Year: 2011

A micro-RNA, miR-155, is overexpressed in many types of cancer cells, including breast cancer, and its role(s) in tumor metastasis has been studied on a very limited basis. Tumor metastasis is a multi-step process with the last step in the process being formation of macroscopic tumor in organs distant from the primary tumor site. This step is the least studied. Here, we report that stable expression of miR-155 in 4T1 breast tumor cells reduces significantly the aggressiveness of tumor cell dissemination as a result of preventing epithelial-to-mesenchymal transition (EMT) of tumor cells in vivo. Further, miR-155 directly suppresses the expression of the transcription factor TCF4, which is an important regulator of EMT. However, when tumor cells are injected directly into the bloodstream, miR-155 remarkably promotes macroscopic tumor formation in the lung. Analysis of gene expression profiling identified a group of genes that are associated with promoting macroscopic tumor formation in the lung. Importantly, most of these genes are overexpressed in epithelial cells. Our findings provide new insight into how miR-155 modulates the development of tumor metastasis. This study suggests that the location of tumor cells overexpressing miR-155 is a critical factor: in mammary fat pads miR-155 prevents tumor dissemination; whereas in the lung miR-155 apparently maintains the epithelial phenotype of tumor cells that is critical for macroscopic tumor formation. © 2011 Macmillan Publishers Limited All rights reserved.


Zhang H.-G.,University of Louisville | Zhang H.-G.,Louisville Veterans Administration Medical Center | Zhuang X.,University of Louisville | Sun D.,University of Alabama at Birmingham | And 3 more authors.
Biotechnic and Histochemistry | Year: 2012

The immune system has been reported to suppress the development and progression of neoplastic lesions; however, the exact mechanisms by which neoplastic lesions and the immune system interact are not well understood. Within the last decade, tiny membrane bound particles, approximately 30-100 nm in diameter, have been observed in the blood and other body fluids. These particles, currently called exosomes, are released from many types of tissues including tumors, and they contain and carry many proteins, and mRNAs and microRNA species. We review here how tumors suppress the immune system, especially by the formation of exosomes. Exosomes released from tumors are carried in part by the vascular system to distant cells, which phagocytose them. Depending on the proteins, mRNAs or microRNAs in the exosomes and the cell type, phagocytosis of exosomes may provide a modulating signal to the cell. In the case of exosomes from tumors, uptake of the exosomes by cells of the immune system has been reported to have three main effects: 1) suppression of the number and activity of natural killer cells, 2) suppression of the activity of T cells and 3) suppression of the number and maturation of mature dendritic cells. © 2012 The Biological Stain Commission.


Ju S.,University of Louisville | Mu J.,University of Louisville | Dokland T.,University of Alabama at Birmingham | Zhuang X.,University of Louisville | And 13 more authors.
Molecular Therapy | Year: 2013

Food-derived exosome-like nanoparticles pass through the intestinal tract throughout our lives, but little is known about their impact or function. Here, as a proof of concept, we show that the cells targeted by grape exosome-like nanoparticles (GELNs) are intestinal stem cells whose responses underlie the GELN-mediated intestinal tissue remodeling and protection against dextran sulfate sodium (DSS)-induced colitis. This finding is further supported by the fact that coculturing of crypt or sorted Lgr5 + stem cells with GELNs markedly improved organoid formation. GELN lipids play a role in induction of Lgr5 + stem cells, and the liposome-like nanoparticles (LLNs) assembled with lipids from GELNs are required for in vivo targeting of intestinal stem cells. Blocking β-catenin-mediated signaling pathways of GELN recipient cells attenuates the production of Lgr5 + stem cells. Thus, GELNs not only modulate intestinal tissue renewal processes, but can participate in the remodeling of it in response to pathological triggers. © The American Society of Gene & Cell Therapy.


Wang Q.,Louisville Veterans Administration Medical Center | Wang Q.,University of Louisville | Ren Y.,Huaian First Peoples Hospital | Mu J.,University of Louisville | And 8 more authors.
Cancer Research | Year: 2015

Inflammation is a hallmark of cancer. Activated immune cells are intrinsically capable of homing to inflammatory sites. Using three inflammatory-driven disease mouse models, we show that grapefruit-derived nanovectors (GNV) coated with inflammatory-related receptor enriched membranes of activated leukocytes (IGNVs) are enhanced for homing to inflammatory tumor tissues. Blocking LFA-1 or CXCR1 and CXCR2 on the IGNVs significantly inhibits IGNV homing to the inflammatory tissue. The therapeutic potential of IGNVs was further demonstrated by enhancing the chemotherapeutic effect as shown by inhibition of tumor growth in two tumor models and inhibiting the inflammatory effects of dextran sulfate sodium-induced mouse colitis. The fact that IGNVs are capable of homing to inflammatory tissue and that chemokines are overexpressed in diseased human tissue provides the rationale for using IGNVs to more directly deliver therapeutic agents to inflammatory tumor sites and the rationale for the use of IGNVs as treatment for certain cancers in personalized medicine. © 2015 American Association for Cancer Research.


Wang Q.,Louisville Veterans Administration Medical Center | Wang Q.,University of Louisville | Zhuang X.,University of Louisville | Mu J.,University of Louisville | And 9 more authors.
Nature Communications | Year: 2013

Although the use of nanotechnology for the delivery of a wide range of medical treatments has potential to reduce adverse effects associated with drug therapy, tissue-specific delivery remains challenging. Here we show that nanoparticles made of grapefruit-derived lipids, which we call grapefruit-derived nanovectors, can deliver chemotherapeutic agents, short interfering RNA, DNA expression vectors and proteins to different types of cells. We demonstrate the in vivo targeting specificity of grapefruit-derived nanovectors by co-delivering therapeutic agents with folic acid, which in turn leads to significantly increasing targeting efficiency to cells expressing folate receptors. The therapeutic potential of grapefruit-derived nanovectors was further demonstrated by enhancing the chemotherapeutic inhibition of tumour growth in two tumour animal models. Grapefruit-derived nanovectors are less toxic than nanoparticles made of synthetic lipids and, when injected intravenously into pregnant mice, do not pass the placental barrier, suggesting that they may be a useful tool for drug delivery. © 2013 Macmillan Publishers Limited. All rights reserved.


Wang B.,University of Louisville | Zhuang X.,University of Louisville | Deng Z.-B.,University of Louisville | Jiang H.,University of Louisville | And 10 more authors.
Molecular Therapy | Year: 2014

The gut mucosal immune system is considered to play an important role in counteracting potential adverse effects of food-derived antigens including nanovesicles. Whether nanovesicles naturally released from edible fruit work in a coordinated manner with gut immune cells to maintain the gut in a noninflammatory status is not known. Here, as proof of concept, we demonstrate that grapefruit-derived nanovesicles (GDNs) are selectively taken up by intestinal macrophages and ameliorate dextran sulfate sodium (DSS)-induced mouse colitis. These effects were mediated by upregulating the expression of heme oxygenase-1 (HO-1) and inhibiting the production of IL-1β and TNF-α in intestinal macrophages. The inherent biocompatibility and biodegradability, stability at wide ranges of pH values, and targeting of intestinal macrophages led us to further develop a novel GDN-based oral delivery system. Incorporating methotrexate (MTX), an anti-inflammatory drug, into GDNs and delivering the MTX-GDNs to mice significantly lowered the MTX toxicity when compared with free MTX, and remarkably increased its therapeutic effects in DSS-induced mouse colitis. These findings demonstrate that GDNs can serve as immune modulators in the intestine, maintain intestinal macrophage homeostasis, and can be developed for oral delivery of small molecule drugs to attenuate inflammatory responses in human disease. © The American Society of Gene & Cell Therapy.


Foulks G.N.,University of Louisville | Foulks G.N.,Louisville Veterans Administration Medical Center | Borchman D.,University of Louisville
Eye and Contact Lens | Year: 2010

Objective: To recount the historic evaluation of meibomian gland dysfunction (MGD) and describe new techniques to monitor disease and therapy. Methods: A review of the literature regarding the description of MGD and the role of abnormalities of meibomian gland secretion in health and disease. Results: Meibomian gland dysfunction is a common clinical condition and is a major cause of evaporative dry eye with associated discomfort, visual disturbance, and contact lens intolerance. Despite the early description of the anatomy and physiology of the meibomian gland, recognition of the importance of the MGD and particularly therapeutic options to treat it has been limited. Conclusions: Improved methods of spectroscopic and chemical analysis of the meibomian gland secretion in health and disease are providing a better understanding of the physical and chemical abnormalities of the meibomian gland secretions and are allowing better evaluation of medical therapies. © 2010 Lippincott Williams & Wilkins.

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