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Effects of Prostaglandin E2 Receptors and G Protein Coupled Signal Transduction on Synoviocytes of Rats with Adjuvant Arthritis and the Effect of Total Glucosides of Paeony

Author: XuHongMei
Tutor: WeiWei
School: Anhui Medical University,
Course: Pharmacology
Keywords: Adjuvant arthritis Total Glucosides of Peony Prostaglandin E2 Synovial cells Acceptor G protein Signal Transduction
CLC: R285.5
Type: PhD thesis
Year: 2006
Downloads: 245
Quote: 0
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Abstract


Rheumatoid arthritis (rheumatoid arthritis, RA) is a local and systemic inflammation cause joint damage is characterized by chronic autoimmune disease is a common disease worldwide, China's incidence rate of 0.3% to 0.4%, Western countries, the incidence rate of approximately 1%, mainly chronic synovitis, a variety of inflammatory cell infiltration, progressive destruction of articular cartilage and bone tissue, new blood vessels accompanied by significant hyperplasia and systemic inflammation occurred not treatment of RA by the system can be repeated persistent for many years, eventually leading to joint deformity and loss of function of the varying degrees of. Due to causes and pathological mechanisms of the pathogenesis of RA is far from being clarified for clinical chemical treatment of RA drugs are mainly used to control the symptoms of some drugs can slow the disease process, but the slow onset, requiring long-term medication, often appear more serious adverse reactions, so there is no ideal in the clinical treatment of RA drug. Effective parts - TGP glycosides (total the glucosides ofpaeony TGP), extracted from the dried roots of traditional Chinese medicine Radix better clinical treatment of RA, and adverse reactions. Our group's earlier studies found that the TGP carrageenan-induced rat acute inflammation and adjuvant-induced arthritis (adjuvantarthritis, AA) rat primary, secondary inflammation inhibited: the immune cells and cells cytokines such as interleukin (IL) -1 (interleukin-1, IL-1), white interleukin -2 (interleukin-2, IL-2) and tumor necrosis factor-α (tumor necrosis factorα, TNFα) and other functional dependencies hypoxia. Subsequent studies found the the AA rat synovial cells, the inhibitory G protein α subunit (inhibitoryαsubunit increase of G protein, Gαi) mRNA expression activated G protein α subunit (stimulatoryαsubunit of G protein Gαs) mRNA expression reduced, PGE 2 levels, decreased production of cyclic adenosine monophosphate (cyclic adenosine monophosphate, cAMP), hyperthyroidism proliferation of synovial cells, G protein-AC-cAMP signal transduction pathway mediated the pathogenesis of AA rats, further research found, TGP can reduce the AA in synovial cells secrete prostaglandin E 2 (prostaglandins E 2 , PGE 2 ), inhibition of fibroblast-like synovial cells (fibroblast-likesynoviocytes, FLS) excessive proliferation; TGP vitro administration inhibit recombinant rat IL-1α (recombinantrat IL-1α, rIL-1α) stimulus AA rats FLS Gαi1, Gαi2 and Gαi3 expression; may reduce pertussis toxin (pertussis by interleukin-1β (interleukin-1β, IL-1β) stimulation of collagen-induced arthritis (collageninduced arthritis, CIA) rat FLS toxin, PT)-catalyzed ADP-ribosylation, increase the levels of cholera toxin (cholera toxin, CT)-catalyzed ADP-ribosylation level, regulating the activity of the G protein. PGE 2 and the pathogenesis of RA are closely related to it and its corresponding receptor (prostaglandins E 2 receptors, EP) combined with the G protein-coupled activation of G protein signaling pathway caused by changes in intracellular cAMP levels, resulting in a wide range of effects, while the PGE 2 receptors levels change Gαi, Gαs expression changes and Gαs / Gαi balance disorders are will affect to the level of intracellular cAMP. So, TGP whether acting on these links, which play its therapeutic effects of RA? Therefore, the experiments using rat adjuvant arthritis model, synovial cells were observed object probe into AA in synovial cells PGE 2 -EP-G protein-coupled signal path changes as well as the role of TGP. Objective: According to TGP AA rats joint swelling, synovial pathomorphological improvement, analysis TGP synovial cell secretory function and joint swelling, cell proliferation and cAMP levels, and by observing the the TGP pair of PGE < sub> 2 stimulus FLS IL-1β, cAMP level, clear PGE 2 impact on the AA rats synovial cell proliferation; AA onset of target cells - - synovial cells of PGE 2 receptor as a breakthrough the the PGE select synovial cell 2 -EP-G protein-cAMP signal transduction as the starting point to analyze TGP whether by affecting the EP receptors in the the AA rats synovial cells and synovial cells of G protein-cAMP signaling pathway plays a role in inhibiting excessive proliferation of synovial cells. Methods: The rat paw intradermal injection of Freund's complete adjuvant (Freund's complete Adjuvant, FCA) induced rat AA model: TGP 25,50,100 mg · kg -1 treatment administered ( ig, d14 ~ d21), of Tripterygium Glycosides (GTW) 8 mg · kg -1 as a positive control. Measure the secondary side foot volume method paw swelling; the optical microscope joint histopathological changes; mouse thymocyte proliferation Determination of synovial cells to produce IL-1 levels; radioimmunoassay method for the determination of synovial cells the PGE 2 < / sub>, cAMP, TNFα level; the MTT assay FLS proliferation reaction. Gαs, Gαi1, EP subtypes EP2 and EP4 expression using Western blot analysis of synovial tissue; immunohistochemical assay synovial tissue expression of Gαs, Gαi1; radioimmunoassay method for the determination of PGE 2 stimulate AA in synovial cells produce IL-1β and cAMP levels. The joint pathology detect with hematoxylin - eosin (hematoxylin-erosin, HE) staining detected by immunohistochemistry SP method. Results: 1.TGP alleviate the AA rats joint swelling and its inhibit synovial cell secretion of PGE 2 , of IL-1 and TNFα levels are closely related to, increase intracellular cAMP levels play suppression effect of excessive synovial proliferation an important aspect of the injection of FCA induced AA model, the performance of the secondary inflammatory response: contralateral and forelimb joint swelling, ear, tail, inflammatory nodules, erythema, and movement disorder symptoms. The AA rats joint pathological changes mainly as follows: thickening of the synovial tissue, composed of 4 to 6 layers of synovial cells, synovial cells were mostly oval, another part of the synovial cells showed villous hyperplasia; tissues around joints congestion, edema, inflammatory cell infiltration; damage to the articular cartilage, exfoliation, proliferation of collagen fibers, significant pannus formation. TGP (50,100 mg · kg -1 , ig, d14 ~ d21) can alleviate the paw swelling of AA rats; microscopic examination found that the AA rat synovial hyperplasia weakened, lymphocytes reduce infiltration, pannus formation reducing the extent of cartilage damage relief. TGP administered in vivo (50,100 mg · kg -1 , ig, d14 to d21) can significantly inhibit AA in synovial cell culture the supernatant excessive PGE 2 , IL-1 and TNFα levels, correlation analysis showed that TGP relieve the AA rats joint swelling and its inhibition of synovial cells of PGE 2 , of IL-1 and TNFα is closely related to the correlation coefficients were 0.9696 , 0.9639 and 0.9384. The TGP administered in vivo (50,100 mg · kg -1 , ig, d14 ~ d21) and in vitro the administration (62.5,125,250 μg · ml -1 ) can inhibit AA rats the FLS excessive proliferation, elevated intracellular cAMP levels correlation analysis showed TGP inhibit the FLS the proliferation of AA rats their increase intracellular cAMP levels are closely related to the correlation coefficients were -0.9956, -0.9877. 2. inhibition of PGE , TGP inhibit the proliferation of synovial cells, one of the characteristics of PGE 2 stimulation of fibroblast-like synovial cells secrete IL-1β, regulating cAMP levels 2 (10 -7 M) in vitro stimulation of FLS, a short period of time (1 ~ 4h) allows cAMP levels, while PGE 2 continuous stimulation resulted in a significant decline in the levels of cAMP; TGP vitro administration (62.5,125,250 μg · ml -1 ) can be different degrees suppression of PGE 2 continued to stimulate the generation of IL-1β, improve the FLS in cAMP levels, indicating that inhibition AA rat synovial cell hyperfunction secretory function is an important feature of the TGP inhibition of proliferation. PGE Recovery AA rat synovial cell 2 -EP-G protein-cAMP signal transduction is an important mechanism of TGP inhibit synovial proliferation detected by Western blot results found TGP body to drugs (50,100 mg · kg -1 , ig, d14 to d21) significantly inhibited the expression of AA in synovial tissue Gαi1, promote Gαs expression, to restore balance Gαs / Gαi promote the EP Asia type EP2, EP4 expression, suggesting: regulating the expression of EP2, EP4, to maintain the balance of Gαs / Gαi recovery of PGE 2 -EP-G protein-cAMP normal signal transduction may TGP suppression one of the important mechanisms of AA rats synovial proliferation. Conclusion: 1.TGP reduce synovial cell secretion of PGE 2 of IL-1 and TNFα levels increase intracellular cAMP levels is the main role to ease the AA rats joint swelling, inhibit the excessive proliferation of synovial 2.TGP the inhibiting of PGE 2 stimulate FLS produce IL-1β, enhance PGE 2 continued to stimulate cAMP levels reduced its inhibition of AA rats secretory function of synovial cell hyperfunction produce the anti-proliferative effect of important characteristics. 3.TGP able to inhibit the Gαi1 the expression of the AA rats synovial tissue, raised Gαs expression of EP2 and EP4, restore balance Gαs / Gαi so elevated intracellular cAMP levels, thereby reducing the proliferation of synovial cells and secretion, suggesting that the adjustment of PGE 2 -EP-G protein-cAMP signal transduction balance, may inhibit one of the important mechanisms of synovial proliferation TGP play.

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