College of Agriculture & Natural Resources
Permanent URI for this communityhttp://hdl.handle.net/1903/1598
The collections in this community comprise faculty research works, as well as graduate theses and dissertations.
Browse
3 results
Search Results
Item Identification and functional analysis of a biflavone as a novel inhibitor of TRPV4-dependent atherogenic process in macrophages(2021) Alharbi, Mazen Obaid; Rahaman, Shaik O.; Nutrition; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Cardiovascular disease is the major cause of death throughout the world. Atherosclerosis, a chronic inflammatory disease of large arteries, is the major contributor to the growing burden of cardiovascular disease-related mortality and morbidity throughout the world. During early atherogenesis, as a result of inflammation and endothelial dysfunction, monocytes transmigrate into the aortic intimal areas, and differentiate into lipid-laden macrophage foam cells, a critical process in atherosclerosis. Numerous natural compounds such as flavonoids and polyphenols are known to have anti-inflammatory and anti-atherogenic properties. Transient receptor potential vanilloid 4 (TRPV4), a non-selective Ca2+-permeant ion channel and a mechanosensor, is widely expressed in diverse cell types including macrophages. Accumulating reports from our laboratory and others on TRPV4 recognized this plasma membrane receptor/channel as an essential modulator of various physiological functions in cardiac, pulmonary, urinary, skeletal, digestive system, and central and peripheral nervous systems. Thus, it is expected that aberrant regulation of TRPV4 activity may lead to multiple pathological conditions such as cardiovascular disease, pulmonary disease, inflammation, neurological disorders, inflammatory bowel disease and wound healing. Previous studies by our group and others have reported that TRPV4 can be activated by numerous mechanical and biochemical stimuli including shear stress, osmolarity, temperature, and growth factors, as well as by alterations in matrix stiffness in vitro and in vivo. Recently, we reported that oxidized low-density lipoprotein-mediated and matrix stiffness-induced macrophage foam cell formation, a critical pathological process in atherosclerosis, is regulated in a TRPV4-dependent manner. Given that TRPV4 is a mechanosensitive channels and mechanical factors like hypertension, disrupted laminar flow of blood, and matrix stiffening are recognized pro-atherogenic factors, makes TRPV4 an important target for therapeutic intervention of atherosclerosis. The objectives of this proposal is to: i) identify natural inhibitor (s) of TRPV4 utilizing a fluorometric imaging plate reader-supported Ca2+ influx assay, ii) functionally characterize the identified compound, and iii) determine the mechanisms by which the identified compound blocks pro-atherogenic/inflammatory TRPV4 activity in macrophages. We expect that the results of this study may strengthen the rationale for the use of natural compounds for developing therapeutic and/or chemopreventive molecules.Item THE PROATHEROGENIC ROLE OF THE TRPV4 CALCIUM-PERMEABLE CHANNEL IN MACROPHAGES(2016) Merth, Michael; Rahaman, Shaid O; Nutrition; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Atherosclerosis is a multi-faceted chronic disease and one of the leading causes of cardiovascular diseases which attribute to 28.2% of all-cause mortality worldwide. Central tenets of atherogenesis are macrophage passage and transformation to foam cells. It is known that numerous macrophage membrane proteins regulate this process by controlling properties such as migration and binding and uptake of oxidized lipids. The focus of this study is to identify mechanisms by which the transient receptor potential (TRP) channel of the vanilloid subfamily, TRPV4, a calcium-permeable channel, regulates proatherogenic macrophage functions. The findings show TRPV4 is expressed and functional in macrophages, TRPV4 modulates macrophage migratory characteristics, oxidized low-density lipoprotein (oxLDL) uptake and foam cell formation is reliant on TRPV4-elicited Ca2+ influx, and the physiological inflammatory stimulus of lipopolysaccharide can mediate TRPV4 function. These results identified previously unknown components to macrophage migration and foam cell development. Collectively, these discoveries associate the TRPV4 channel with atherogenesis by identifying new regulators for macrophage phagocytosis and migration that are essential to atherosclerosis development.Item THE FUNCTIONAL REGULATION OF FCRN EXPRESSION AND FCRN-MEDIATED ANTIGEN PRESENTATION(2009) Liu, Xindong; Zhu, Xiaoping; Animal Sciences; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The neonatal Fc receptor for IgG (FcRn), a major histocompatibility complex (MHC) class I-related molecule, plays an important role in IgG transport and protection. The transport of IgG across epithelial and endothelial barriers and the IgG homeostasis maintained by FcRn contributes to the effective humoral immunity. Thus, the level of FcRn itself will affect the IgG-associated immune responses. Although FcRn is expressed in a variety of tissues and cell types, the extent to which FcRn expression is regulated by immunological and inflammatory events remains unknown.I showed here that FcRn was up-regulated by the stimulation of inflammatory cytokines or Toll-like receptor ligands in human peripheral blood mononuclear cell (PBMC) and THP-1 cell line. By chromatin immunoprecipitation, I identified three NF-κB binding sites within introns 2 and 4 of the human FcRn gene. These intronic binding sites boost FcRn transcription activities through looping with the promoter region. In contrast, FcRn expression was down-regulated by Th1 cytokine IFN-γ, and the down-regulation of FcRn was not caused by apoptosis or the instability of FcRn mRNA. It has been demonstrated that IFN-γ activated STAT1 bound with GAS sequence in human FcRn promoter, and which blocked the transcriptional machinery. Fc gamma receptors (FcγRs) expressed in macrophages (MФ) and dendritic cells (DCs) can mediate antigen presentation in both MHC class II and MHC class I pathways. We tested here the role for FcRn in antigen presentation of IgG-restricted Immune complexes (ICs). It was observed that the expression of FcRn in MФ, but not in DC enhanced the phagosomal ICs antigen presentation to CD4 T cells. A low pH value in phgosome of MФ facilitated FcRn binding to ICs, stabilizing the antigens and promoting the efficient MHC II-peptide assembly. However, the alkalized phagosomes in DC failed FcRn to enhance the antigen presentation of ICs.