1.Research progress on the biological regulatory function of lysophosphatidic acid in bone tissue cells.
Xiang-Nan WU ; Yuan-Yuan MA ; Zhi-Chao HAO ; Hang WANG
West China Journal of Stomatology 2020;38(3):324-329
Lysophosphatidic acid (LPA) is a small phospholipid that is present in all eukaryotic tissues and blood plasma. As an extracellular signaling molecule, LPA mediates many cellular functions by binding to six known G protein-coupled receptors and activating their downstream signaling pathways. These functions indicate that LPA may play important roles in many biological processes that include organismal development, wound healing, and carcinogenesis. Recently, many studies have found that LPA has various biological effects in different kinds of bone cells. These findings suggest that LPA is a potent regulator of bone development and remodeling and holds promising application potential in bone tissue engineering. Here, we review the recent progress on the biological regulatory function of LPA in bone tissue cells.
Biological Phenomena
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Bone and Bones
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Lysophospholipids
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Receptors, Lysophosphatidic Acid
2.Role of TAZ in Lysophosphatidic Acid-Induced Migration and Proliferation of Human Adipose-Derived Mesenchymal Stem Cells.
Won Min MO ; Yang Woo KWON ; Il Ho JANG ; Eun Jung CHOI ; Sang Mo KWON ; Jae Ho KIM
Biomolecules & Therapeutics 2017;25(4):354-361
Transcriptional co-activator with a PDZ-binding motif (TAZ) is an important factor in lysophosphatidic acid (LPA)-induced promotion of migration and proliferation of human mesenchymal stem cells (MSCs). The expression of TAZ significantly increased at 6 h after LPA treatment, and TAZ knockdown inhibited the LPA-induced migration and proliferation of MSCs. In addition, embryonic fibroblasts from TAZ knockout mice exhibited the reduction in LPA-induced migration and proliferation. The LPA1 receptor inhibitor Ki16425 blocked LPA responses in MSCs. Although TAZ knockdown or knockout did not reduce LPA-induced phosphorylation of ERK and AKT, the MEK inhibitor U0126 or the ROCK inhibitor Y27632 blocked LPA-induced TAZ expression along with the reduction in the proliferation and migration of MSCs. Our data suggest that TAZ is an important mediator of LPA signaling in MSCs in the downstream of MEK and ROCK signaling.
Animals
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Fibroblasts
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Humans*
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Mesenchymal Stromal Cells*
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Mice
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Mice, Knockout
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Phosphorylation
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Receptors, Lysophosphatidic Acid
3.Role of TAZ in Lysophosphatidic Acid-Induced Migration and Proliferation of Human Adipose-Derived Mesenchymal Stem Cells.
Won Min MO ; Yang Woo KWON ; Il Ho JANG ; Eun Jung CHOI ; Sang Mo KWON ; Jae Ho KIM
Biomolecules & Therapeutics 2017;25(4):354-361
Transcriptional co-activator with a PDZ-binding motif (TAZ) is an important factor in lysophosphatidic acid (LPA)-induced promotion of migration and proliferation of human mesenchymal stem cells (MSCs). The expression of TAZ significantly increased at 6 h after LPA treatment, and TAZ knockdown inhibited the LPA-induced migration and proliferation of MSCs. In addition, embryonic fibroblasts from TAZ knockout mice exhibited the reduction in LPA-induced migration and proliferation. The LPA1 receptor inhibitor Ki16425 blocked LPA responses in MSCs. Although TAZ knockdown or knockout did not reduce LPA-induced phosphorylation of ERK and AKT, the MEK inhibitor U0126 or the ROCK inhibitor Y27632 blocked LPA-induced TAZ expression along with the reduction in the proliferation and migration of MSCs. Our data suggest that TAZ is an important mediator of LPA signaling in MSCs in the downstream of MEK and ROCK signaling.
Animals
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Fibroblasts
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Humans*
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Mesenchymal Stromal Cells*
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Mice
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Mice, Knockout
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Phosphorylation
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Receptors, Lysophosphatidic Acid
4.Promising Pharmacological Directions in the World of Lysophosphatidic Acid Signaling.
Nicole C STODDARD ; Jerold CHUN
Biomolecules & Therapeutics 2015;23(1):1-11
Lysophosphatidic acid (LPA) is a signaling lipid that binds to six known lysophosphatidic acid receptors (LPARs), named LPA1-LPA6. These receptors initiate signaling cascades relevant to development, maintenance, and healing processes throughout the body. The diversity and specificity of LPA signaling, especially in relation to cancer and autoimmune disorders, makes LPA receptor modulation an attractive target for drug development. Several LPAR-specific analogues and small molecules have been synthesized and are efficacious in attenuating pathology in disease models. To date, at least three compounds have passed phase I and phase II clinical trials for idiopathic pulmonary fibrosis and systemic sclerosis. This review focuses on the promising therapeutic directions emerging in LPA signaling toward ameliorating several diseases, including cancer, fibrosis, arthritis, hydrocephalus, and traumatic injury.
Arthritis
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Autoimmune Diseases
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Fibrosis
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Hydrocephalus
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Idiopathic Pulmonary Fibrosis
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Pathology
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Pharmacology
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Receptors, Lysophosphatidic Acid
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Scleroderma, Systemic
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Sensitivity and Specificity
5.Lysophosphatidic acid enhances breast cancer cells-mediated osteoclastogenesis.
Ju Suk NAM ; Ashish Ranjan SHARMA ; Lich Thi NGUYEN ; Supriya JAGGA ; Yeon Hee LEE ; Garima SHARMA ; Sang Soo LEE
The Korean Journal of Physiology and Pharmacology 2018;22(5):503-511
Lysophosphatidic acid (LPA) is known to play a critical role in breast cancer metastasis to bone. In this study, we tried to investigate any role of LPA in the regulation of osteoclastogenic cytokines from breast cancer cells and the possibility of these secretory factors in affecting osteoclastogenesis. Effect of secreted cytokines on osteoclastogenesis was analyzed by treating conditioned media from LPA-stimulated breast cancer cells to differentiating osteoclasts. Result demonstrated that IL-8 and IL-11 expression were upregulated in LPA-treated MDA-MB-231 cells. IL-8 was induced in both MDA-MB-231 and MDA-MB-468, however, IL-11 was induced only in MDA-MB-231, suggesting differential LPARs participation in the expression of these cytokines. Expression of IL-8 but not IL-11 was suppressed by inhibitors of PI3K, NFkB, ROCK and PKC pathways. In the case of PKC activation, it was observed that PKCδ and PKCμ might regulate LPA-induced expression of IL-11 and IL-8, respectively, by using specific PKC subtype inhibitors. Finally, conditioned Medium from LPA-stimulated breast cancer cells induced osteoclastogenesis. In conclusion, LPA induced the expression of osteolytic cytokines (IL-8 and IL-11) in breast cancer cells by involving different LPA receptors. Enhanced expression of IL-8 by LPA may be via ROCK, PKCu, PI3K, and NFkB signaling pathways, while enhanced expression of IL-11 might involve PKCδ signaling pathway. LPA has the ability to enhance breast cancer cells-mediated osteoclastogenesis by inducing the secretion of cytokines such as IL-8 and IL-11.
Breast Neoplasms*
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Breast*
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Culture Media, Conditioned
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Cytokines
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Interleukin-11
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Interleukin-8
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Neoplasm Metastasis
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Osteoclasts
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Receptors, Lysophosphatidic Acid
6.Lysophosphatidic acid receptors and the downstream signaling pathways in regulation of cardiac cell growth.
Acta Physiologica Sinica 2007;59(5):619-627
Lysophosphatidic acid (LPA) is a bioactive phospholipid messenger with multiple biological functions, including induction of neurite retraction, stress fiber formation, promotion of platelet aggregation and stimulation of smooth muscle contraction and cell proliferation. LPA exerts various biological functions through G protein-coupled receptors and the downstream cellular signaling pathways. LPA and its receptors may also play important roles in the heart since several LPA receptor subtypes exist in the heart and especially the level of LPA1 subtype is the second highest, just lower than that in the brain. The review was focused on 5 subtypes of LPA receptor, mainly on their tissue expression pattern, coupled G proteins and signal pathways, as well as the roles of LPA and its receptors in regulation of cardiac cell growth.
Animals
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Cell Cycle
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Cell Proliferation
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Cells, Cultured
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Humans
;
Lysophospholipids
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Myocytes, Cardiac
;
physiology
;
Receptors, G-Protein-Coupled
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Receptors, Lysophosphatidic Acid
;
physiology
;
Signal Transduction
7.Activation of Lysophosphatidic Acid Receptor Is Coupled to Enhancement of Ca(2+)-Activated Potassium Channel Currents.
Sun Hye CHOI ; Byung Hwan LEE ; Hyeon Joong KIM ; Sung Hee HWANG ; Sang Mok LEE ; Seung Yeol NAH
The Korean Journal of Physiology and Pharmacology 2013;17(3):223-228
The calcium-activated K+ (BKCa) channel is one of the potassium-selective ion channels that are present in the nervous and vascular systems. Ca2+ is the main regulator of BKCa channel activation. The BKCa channel contains two high affinity Ca2+ binding sites, namely, regulators of K+ conductance, RCK1 and the Ca2+ bowl. Lysophosphatidic acid (LPA, 1-radyl-2-hydroxy-sn-glycero-3-phosphate) is one of the neurolipids. LPA affects diverse cellular functions on many cell types through G protein-coupled LPA receptor subtypes. The activation of LPA receptors induces transient elevation of intracellular Ca2+ levels through diverse G proteins such as Galphaq/11, Galphai, Galpha12/13, and Galphas and the related signal transduction pathway. In the present study, we examined LPA effects on BKCa channel activity expressed in Xenopus oocytes, which are known to endogenously express the LPA receptor. Treatment with LPA induced a large outward current in a reversible and concentration-dependent manner. However, repeated treatment with LPA induced a rapid desensitization, and the LPA receptor antagonist Ki16425 blocked LPA action. LPA-mediated BKCa channel activation was also attenuated by the PLC inhibitor U-73122, IP3 inhibitor 2-APB, Ca2+ chelator BAPTA, or PKC inhibitor calphostin. In addition, mutations in RCK1 and RCK2 also attenuated LPA-mediated BKCa channel activation. The present study indicates that LPA-mediated activation of the BKCa channel is achieved through the PLC, IP3, Ca2+, and PKC pathway and that LPA-mediated activation of the BKCa channel could be one of the biological effects of LPA in the nervous and vascular systems.
Binding Sites
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Egtazic Acid
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Estrenes
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GTP-Binding Proteins
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Ion Channels
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Isoxazoles
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Lysophospholipids
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Naphthalenes
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Oocytes
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Potassium
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Potassium Channels
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Propionates
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Pyrrolidinones
;
Receptors, Lysophosphatidic Acid
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Signal Transduction
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Xenopus
8.Effect of lysophosphatidic acid on differentiation of embryonic neural stem cells into neuroglial cells in rats in vitro.
Acta Physiologica Sinica 2007;59(6):759-764
To study the effect of lysophosphatidic acid (LPA) on the differentiation of embryonic neural stem cells (NSCs) into neuroglial cells in rats in vitro, both oligodendrocytes and astrocytes were detected by their marker proteins galactocerebroside (Gal-C) and glial fibrillary acidic protein (GFAP), respectively, using double-labeling immunocytochemistry. RT-PCR assay was also used for analyzing the expression of LPA receptors in NSCs. Our results showed that: (1) LPA at different concentrations (0.01-3.0 mumol/L) was added to culture medium and cell counting was carried out on the 7th day in all groups. Exposure to LPA led to a dose-dependent increase of oligodendrocytes with the response peaked at 1.0 mumol/L, with an increased percentage of 32.6% (P<0.01) of total cells as compared to that of 8.5% in the vehicle group. (2) LPA showed no effect on the differentiation of NSCs into astrocytes. (3) RT-PCR assay showed that LPA(1) and LPA(3) receptors were strongly expressed while LPA(2) receptor expressed weakly in NSCs. These results suggest that LPA at low concentration might act as an extracellular signal through the receptors in NSCs, mainly LPA(1) and LPA(3) receptors, to promote the differentiation of NSCs into oligodendrocytes, while it exhibits little, if any, conceivable effect on the differentiation of NSCs into astrocytes.
Animals
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Cell Differentiation
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drug effects
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Cells, Cultured
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Lysophospholipids
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pharmacology
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Neural Stem Cells
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cytology
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drug effects
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Neuroglia
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cytology
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Rats
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Receptors, Lysophosphatidic Acid
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metabolism
9.Gintonin, an exogenous ginseng-derived LPA receptor ligand, promotes corneal wound healing.
Hyeon Joong KIM ; Joon Young KIM ; Byung Hwan LEE ; Sun Hye CHOI ; Hyewon RHIM ; Hyoung Chun KIM ; Seoung Yob AHN ; Soon Wuk JEONG ; Minhee JANG ; Ik Hyun CHO ; Seung Yeol NAH
Journal of Veterinary Science 2017;18(3):387-397
Ginseng gintonin is an exogenous ligand of lysophosphatidic acid (LPA) receptors. Accumulating evidence shows LPA helps in rapid recovery of corneal damage. The aim of this study was to evaluate the therapeutic efficacy of gintonin in a rabbit model of corneal damage. We investigated the signal transduction pathway of gintonin in human corneal epithelium (HCE) cells to elucidate the underlying molecular mechanism. We next evaluated the therapeutic effects of gintonin, using a rabbit model of corneal damage, by undertaking histochemical analysis. Treatment of gintonin to HCE cells induced transient increases of [Ca²⁺](i) in concentration-dependent and reversible manners. Gintonin-mediated mobilization of [Ca²⁺](i) was attenuated by LPA1/3 receptor antagonist Ki16425, phospholipase C inhibitor U73122, inositol 1,4,5-triphosphate receptor antagonist 2-APB, and intracellular Ca²⁺ chelator BAPTA-AM. Gintonin facilitated in vitro wound healing in a concentration-dependent manner. When applied as an eye-drop to rabbits with corneal damage, gintonin rapidly promoted recovery. Histochemical analysis showed gintonin decreased corneal apoptosis and increased corneal cell proliferation. We demonstrated that LPA receptor activation by gintonin is linked to in vitro and in vivo therapeutic effects against corneal damage. Gintonin can be applied as a clinical agent for the rapid healing of corneal damage.
Apoptosis
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Cell Proliferation
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Corneal Injuries
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Epithelium, Corneal
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Humans
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In Vitro Techniques
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Inositol 1,4,5-Trisphosphate
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Mortuary Practice
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Panax
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Rabbits
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Receptors, Lysophosphatidic Acid
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Signal Transduction
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Therapeutic Uses
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Type C Phospholipases
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Wound Healing*
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Wounds and Injuries*
10.Signaling Pathway of Lysophosphatidic Acid-Induced Contraction in Feline Esophageal Smooth Muscle Cells.
Yun Sung NAM ; Jung Sook SUH ; Hyun Ju SONG ; Uy Dong SOHN
The Korean Journal of Physiology and Pharmacology 2013;17(2):139-147
Lysolipids such as LPA, S1P and SPC have diverse biological activities including cell proliferation, differentiation, and migration. We investigated signaling pathways of LPA-induced contraction in feline esophageal smooth muscle cells. We used freshly isolated smooth muscle cells and permeabilized cells from cat esophagus to measure the length of cells. Maximal contraction occurred at 10(-6) M and the response peaked at 30s. To identify LPA receptor subtypes in cells, western blot analysis was performed with antibodies to LPA receptor subtypes. LPA1 and LPA3 receptor were detected at 50 kDa and 44 kDa. LPA-induced contraction was almost completely blocked by LPA receptor (1/3) antagonist KI16425. Pertussis toxin (PTX) inhibited the contraction induced by LPA, suggesting that the contraction is mediated by a PTX-sensitive G protein. Phospholipase C (PLC) inhibitors U73122 and neomycin, and protein kinase C (PKC) inhibitor GF109203X also reduced the contraction. The PKC-mediated contraction may be isozyme-specific since only PKCepsilon antibody inhibited the contraction. MEK inhibitor PD98059 and JNK inhibitor SP600125 blocked the contraction. However, there is no synergistic effect of PKC and MAPK on the LPA-induced contraction. In addition, RhoA inhibitor C3 exoenzyme and ROCK inhibitor Y27632 significantly, but not completely, reduced the contraction. The present study demonstrated that LPA-induced contraction seems to be mediated by LPA receptors (1/3), coupled to PTX-sensitive G protein, resulting in activation of PLC, PKC-epsilon pathway, which subsequently mediates activation of ERK and JNK. The data also suggest that RhoA/ROCK are involved in the LPA-induced contraction.
Amides
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Animals
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Anthracenes
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Antibodies
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Blotting, Western
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Cats
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Cell Proliferation
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Contracts
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Esophagus
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Estrenes
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Flavonoids
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GTP-Binding Proteins
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Indoles
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Isoxazoles
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Maleimides
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Muscle, Smooth
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Myocytes, Smooth Muscle
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Neomycin
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Pertussis Toxin
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Propionates
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Protein Kinase C
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Pyridines
;
Pyrrolidinones
;
Receptors, Lysophosphatidic Acid
;
Type C Phospholipases