93 research outputs found
Potential Use of G Protein-Coupled Receptor-Blocking Monoclonal Antibodies as Therapeutic Agents for Cancers
No full textG protein-coupled receptor GPR19 regulates E-cadherin expression and invasion of breast cancer cells
No full textClose head-to-head juxtaposition of genes favors their coordinate regulation in Drosophila melanogaster
No full textAbstractThis report identifies a large number of gene-pairs in Drosophila melanogaster that share a common upstream region. 877 gene-pairs (∼12% of the genome) are separated by less than 350 bp in a head-to-head orientation. This positional relationship is more highly favored in flies than in other organisms. These gene pairs have a higher correlation of expression than similarly spaced genes that have head-to-tail or tail-to-tail orientations. Thus, the positional arrangement of genes appears to play a significant role in coordinating relative expression patterns and may provide clues for identifying the functions of unknown genes
Potential Therapeutic Applications for Inhibitors of Autotaxin, a Bioactive Lipid-Producing Lysophospholipase D, in Disorders Affecting the Nervous System
No full textStereotyped fetal brain disorganization is induced by hypoxia and requires lysophosphatidic acid receptor 1 (LPA <sub>1</sub> ) signaling
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Fetal hypoxia is a common risk factor that has been associated with a range of CNS disorders including epilepsy, schizophrenia, and autism. Cellular and molecular mechanisms through which hypoxia may damage the developing brain are incompletely understood but are likely to involve disruption of the laminar organization of the cerebral cortex. Lysophosphatidic acid (LPA) is a bioactive lipid capable of cortical influences via one or more of six cognate G protein-coupled receptors, LPA
1–6
, several of which are enriched in fetal neural progenitor cells (NPCs). Here we report that fetal hypoxia induces cortical disruption via increased LPA
1
signaling involving stereotyped effects on NPCs:
N
-cadherin disruption, displacement of mitotic NPCs, and impaired neuronal migration, as assessed both ex vivo and in vivo. Importantly, genetic removal or pharmacological inhibition of LPA
1
prevented the occurrence of these hypoxia-induced phenomena. Hypoxia resulted in overactivation of LPA
1
through selective inhibition of G protein-coupled receptor kinase 2 expression and activation of downstream pathways including G
αi
and Ras-related C3 botulinum toxin substrate 1. These data identify stereotyped and selective hypoxia-induced cerebral cortical disruption requiring LPA
1
signaling, inhibition of which can reduce or prevent disease-associated sequelae, and may take us closer to therapeutic treatment of fetal hypoxia-induced CNS disorders and possibly other forms of hypoxic injury.
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Anti-Inflammatory Effects of Phytochemical Components of Clinacanthus nutans
No full textRecent studies on the ethnomedicinal use of Clinacanthus nutans suggest promising anti-inflammatory, anti-tumorigenic, and antiviral properties for this plant. Extraction of the leaves with polar and nonpolar solvents has yielded many C-glycosyl flavones, including schaftoside, isoorientin, orientin, isovitexin, and vitexin. Aside from studies with different extracts, there is increasing interest to understand the properties of these components, especially regarding their ability to exert anti-inflammatory effects on cells and tissues. A major focus for this review is to obtain information on the effects of C. nutans extracts and its phytochemical components on inflammatory signaling pathways in the peripheral and central nervous system. Particular emphasis is placed on their role to target the Toll-like receptor 4 (TLR4)-NF-kB pathway and pro-inflammatory cytokines, the antioxidant defense pathway involving nuclear factor erythroid-2-related factor 2 (NRF2) and heme oxygenase 1 (HO-1); and the phospholipase A(2) (PLA(2)) pathway linking to cyclooxygenase-2 (COX-2) and production of eicosanoids. The ability to provide a better understanding of the molecular targets and mechanism of action of C. nutans extracts and their phytochemical components should encourage future studies to develop new therapeutic strategies for better use of this herb to combat inflammatory diseases
7H9 blocks activation of S1P<sub>3</sub>.
No full text<p>(A-D) 7H9 blocks S1P<sub>3</sub>-mediated arrestin translocation. β-arrestin (green) is cytosolic in quiescent cells and appears as diffuse labeling (A). Following stimulation with 1 µM S1P (B), arrestin translocates to the plasma membrane and is rapidly internalized into intracellular vesicles (arrows). In contrast, when cells are pre-treated with 1 µg/ml 7H9 arrestin localization is diffuse and cytoplasmic in both the absence (C) and presence (D) of 1 µM S1P. (E-H) 7H9 blocks S1P-dependent internalization of S1P<sub>3</sub>. Epitope-tagged S1P<sub>3</sub> is normally abundant on the plasma membrane (E, arrows), but is internalized into intracellular vesicles (arrowheads) upon stimulation with 1 µM S1P (F). Following pre-treatment of cells with 7H9, S1P<sub>3</sub> remains localized to the plasma membrane in the absence (G) or presence (H) of 1 µM S1P. (I) 7H9 blocks S1P<sub>3</sub>-dependent calcium mobilization. S1P<sub>3</sub>-expressing cells exhibited increased intracellular [Ca<sup>2+</sup>] upon stimulation with 100 nM S1P (blue, antibody control). Cells within the same culture that did not express S1P<sub>3</sub>-EGFP (green, receptor control) showed no change in [Ca<sub>i</sub><sup>2+</sup>]. Similarly, cells expressing S1P<sub>3</sub> that were pre-treated with 7H9 (red, 7H9) also showed no response to 100 nM and 1 µM S1P, but gave a partial response at 5 µM. (J) 7H9 blocks S1P<sub>3</sub>-dependent inhibition of AC. cAMP was measured in S1P<sub>3</sub>-expressing cells by ELISA and normalized to controls. The graph represents the change in cAMP content from unstimulated cells, relative to the change observed in stimulated cells with no 7H9 pre-treatment. *p<0.05, **p<0.01. Error bars = S.E.M.</p
7H9 inhibits development of breast tumor xenografts.
No full text<p>(A) Volumes of subcutaneous MCF7 tumors in nude mice were determined by caliper measurement. (B-C) Photomicrographs showing H&E stained tumors from IgG control (B) and 7H9-treated (C) mice. (D) Volumes of “necrotic” regions were determined by measuring their cross-sectional areas relative to total area of section. *p<0.05.</p
In vitro and in vivo antagonism of a G protein-coupled receptor (S1P3) with a novel blocking monoclonal antibody.
No full textS1P(3) is a lipid-activated G protein-couple receptor (GPCR) that has been implicated in the pathological processes of a number of diseases, including sepsis and cancer. Currently, there are no available high-affinity, subtype-selective drug compounds that can block activation of S1P(3). We have developed a monoclonal antibody (7H9) that specifically recognizes S1P(3) and acts as a functional antagonist.Specific binding of 7H9 was demonstrated by immunocytochemistry using cells that over-express individual members of the S1P receptor family. We show, in vitro, that 7H9 can inhibit the activation of S1P(3)-mediated cellular processes, including arrestin translocation, receptor internalization, adenylate cyclase inhibiton, and calcium mobilization. We also demonstrate that 7H9 blocks activation of S1P(3) in vivo, 1) by preventing lethality due to systemic inflammation, and 2) by altering the progression of breast tumor xenografts.We have developed the first-reported monoclonal antibody that selectively recognizes a lipid-activated GPCR and blocks functional activity. In addition to serving as a lead drug compound for the treatment of sepsis and breast cancer, it also provides proof of concept for the generation of novel GPCR-specific therapeutic antibodies
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