• IMMUNE NETWORK
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• v.3 no.3
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• pp.201-210
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• 2003

Objective: The role of prostaglandin $E_2$ (PGE2) in the etiopathogenesis of immune and inflammatory diseases has become the subject of recent debate. To determine the role of PGE2 in rheumatoid arthritis (RA), we tested the effect of exogenous PGE2 on the production of cyclooxygenase-2 (COX-2) by rheumatoid synoviocytes. Methods: Fibroblast-like synoviocytes (FLS) were prepared from the synovial tissues of RA patients, and cultured in the presence of PGE2. The COX-2 mRNA and protein expression levels were determined by RT-PCR and Western blot analysis, respectively. The PGE2 receptor subtypes in the FLS were analyzed by RT-PCR. Electrophoretic mobility shift assay (EMSA) was used to measure the NF-${\kappa}B$ binding activity for COX-2 transcription. The in vivoeffect of PGE2 on the development of arthritis was also tested in collagen induced arthritis (CIA) animals. Results: PGE2 ($10^{-11}$ to $10^{-5}M$) dose-dependently inhibited the expression of COX-2 mRNA and the COX-2 protein stimulated with IL-$1{\beta}$, but not COX-1 mRNA. NS-398, a selective COX-2 inhibitor, displayed an additive effect on PGE2-induced COX-2 downregulation. The FLS predominantly expressed the PGE2 receptor (EP) 2 and EP4, which mediated the COX-2 suppression by PGE2. Treatment with anti-IL-10 monoclonal antibodies partially reversed the PGE2-induced suppression of COX-2 mRNA, suggesting that IL-10 may be involved in modulating COX-2 by PGE2. Experiments using an inducer and an inhibitor of cyclic AMP (cAMP) suggest that cAMP is the major intracellular signal that mediates the regulatory effect of PGE2 on COX-2 expression. EMSA revealed that PGE2 inhibited the binding of NF-${\kappa}B$ in the COX-2 promoter via a cAMP dependent pathway. In addition, a subcutaneous injection of PGE2 twice daily for 2 weeks significantly reduced the incidence and severity of CIA as well as the production of IgG antibodies to type II collagen. Conclusion: Our data suggest that overproduced PGE2 in the RA joints may function as an autocrine regulator of its own synthesis by inhibiting COX-2 production and may, in part, play an anti-inflammatory role in the arthritic joints.

• Journal of Life Science
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• v.28 no.4
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• pp.465-471
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• 2018

Bee pollen is one of many types of alternative remedies, and it has been used for a long time throughout the world. It has numerous health effects, including antifungal, antibacterial, and antioxidant properties, immune modulation, enhanced cell proliferation, and even anti-carcinogenic effects. This study was designed to elucidate the effects of bee pollen on benign prostatic hyperplasia in rodents. For this experiment, we used nano-sized bee pollen produced through wet-grinding technology, thereby the extraction efficiency of the active ingredients in the bee pollen was significantly enhanced. First, We found that nano-sized bee pollen significantly reduced the size of prostates enlarged by chronic testosterone administration. In addition, nano-sized bee pollen significantly reduced the plasma concentration of the prostate-specific antigen (PSA). Interestingly, nano-sized bee pollen did not reduce the testosterone-induced increase in the plasma concentration of prostaglandin $E_2$ ($PGE_2$). The beneficial effects of nano-sized bee pollen in reducing both the size of the prostate and the plasma concentration of PSA was comparable to that of dutasteride. Finally, nano-sized bee pollen did not cause damage in LNCaP cells which are androgen-sensitive human prostate adenocarcinoma cells. Together, these data indicate that nano-sized bee pollen may be able to be used as a good alternative remedy for the treatment of benign prostatic hyperplasia.

• Molecules and Cells
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• v.37 no.12
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• pp.899-906
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• 2014

Prostaglandin $E_2$ ($PGE_2$) promotes tumor-persistent inflammation, frequently resulting in cancer. Curcumin is a diphenolic turmeric that inhibits carcinogenesis and induces apoptosis. $PGE_2$ inhibits curcumin-induced apoptosis; however, the underlying inhibitory mechanisms in colon cancer cells remain unknown. The aim of the present study is to investigate the survival role of $PGE_2$ and whether addition of exogenous $PGE_2$ affects curcumininduced cell death. HCT-15 cells were treated with curcumin and $PGE_2$, and protein expression levels were investigated via Western blot. Reactive oxygen species (ROS) generation, lipid peroxidation, and intracellular glutathione (GSH) levels were confirmed using specific dyes. The nuclear factor-kappa B ($NF-{\kappa}B$) DNA-binding was measured by electrophoretic mobility shift assay (EMSA). $PGE_2$ inhibited curcumin-induced apoptosis by suppressing oxidative stress and degradation of PARP and lamin B. However, exposure of cells to the EP2 receptor antagonist, AH6809, and the PKA inhibitor, H89, before treatment with $PGE_2$ or curcumin abolished the protective effect of $PGE_2$ and enhanced curcumin-induced cell death. $PGE_2$ activates PKA, which is required for cAMP-mediated transcriptional activation of CREB. $PGE_2$ also activated the Ras/Raf/Erk pathway, and pretreatment with PD98059 abolished the protective effect of $PGE_2$. Furthermore, curcumin treatment greatly reduced phosphorylation of CREB, followed by a concomitant reduction of $NF-{\kappa}B$ (p50 and p65) subunit activation. $PGE_2$ markedly activated nuclear translocation of $NF-{\kappa}B$. EMSA confirmed the DNA-binding activities of $NF-{\kappa}B$ subunits. These results suggest that inhibition of curcumin-induced apoptosis by $PGE_2$ through activation of PKA, Ras, and $NF-{\kappa}B$ signaling pathways may provide a molecular basis for the reversal of curcumin-induced colon carcinoma cell death.

• The Korea Journal of Herbology
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• v.20 no.2
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• pp.43-53
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• 2005

Objective : The use of herbal therapy is becoming an increasingly attractive approach for the treatment of various inflammatory disorders. The Alpiniae officinari Rhizoma is popular in Aisa as a traditional herbal medicine. Alpiniae officinari Rhizoma is a species of the ginger family(Zingiberacease). Method : This study was performed to investigate the anti-inflammatory effect of Alpiniae officinari Rhizoma extract by the methods of 'carrageenan induced paw edema' and 'Lipopolysaccharide-induced inflammatory mediators in mouse macrophage RAW 264.7 cells'. Result : We suggest that Alpiniae officinari Rhizoma extract decreased paw volume induced by plantar injection of carrageenan. Also Alpiniae officinari Rhizoma extract inhibited nitric oxide, prostaglandin $E_2$ production and induced nitric oxide synthase, cyclooxygenase-2 protein expression in Mouse macrophage RAW 264.7 cells stimulated with lipopolysaccharide. Conclusion : This study shows that Alpinia officinari Rhizoma extract seems to have anti-inflammatory effect by inhibition of nitric oxide, prostaglandin $E_2$ production and nitric oxide synthase, cyclooxygenase-2 protein expression.

• Herbal Formula Science
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• v.16 no.2
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• pp.115-131
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• 2008

실험목적 : 빈소산은 11가지 생약으로 구성된 복합 한약 처방으로 관절염을 포함한 다양한 염증성 질환의 치료제로 사용되어 왔으나, 관절염에 대한 직접적인 효력평가는 찾아 보기 힘들다. 따라서 본 실험에서는 빈소산 추출물이 Freund's complete adjuvant (FCA)로 유발된 rat 류마티스성 관절염에 미치는 치료 효과를 dexamethasone (15mg/kg, 복강 투여) 의 효과와 비교 평가하였다. 실험방법 : 류마티스성 관절염은 FCA (10mg in 1ml paraffin oil 0.1ml/rats)를 좌측 후지에 피내 투여하여 유발하였다. 실험동물은 Wistar 랫트를 사용하였고, FCA 투여 14일 후 유사한 무릎관절 둘레를 나타내는 류마티스성 관절염 유발 rat와 정상 rat 및 실험군을 그룹당 9마리씩 나누었다. 실험동물은 100 또는 200mg/kg의 빈소산 추출물을 FCA 투여 14일 후부터 14일간 경구 투여하였으며, dexamethasone은 15mg/kg 농도로 복강 투여한 다음, 희생하여, 체중, 연골내 collagen 함량 및 chondroitin sulphate, heparin sulphate 및 hyaluronic acid와 같은 뼈내 glycosaminoglycan 함량의 변화를 각각 관찰하였다. 실험결과는 항염 효과가 이미 입증되어 있는 dexamethasone 15mg/kg 복강 투여군과 비교하였다. 결과 : FCA 투여는 현저한 체중, 연골내 collagen 함량 및 chondroitin sulphate, heparin sulphate 및 hyaluronic acid와 같은 뼈내 glycosaminoglycan 함량의 감소와 함께 유발 관절 둘레 및 조직내 prostaglandin $E_2$의 증가와 같은 전형적인 류마티스성 염증을 초래하였으나, 이러한 류마티스성 관절염 소견은 dexamethasone 및 모든 용량의 빈소산 추출물 투여에 의해 현저히 억제되었으며, 특히 빈소산 투여군에서는 투여 용량 의존적인 감소가 인정되었다. 결론 : 이상에서 빈소산 추출물은 투여 용량 의존적인 prostaglandin $E_2$ 억제를 매개하여 FCA 유발 류마티스성 관절염에 대한 치료 효과를 나타내는 것으로 관찰되었다. 따라서 새로운 관절염에 대한 치료제로서 개발 가능성이 있을 것으로 판단된다. 한편 빈소산 추출물은 주로 prostaglandin $E_2$ 억제작용에 의해 항염 효과를 나타내는 것으로 관찰되었으나, 금후 다른 작용기전에 대한 연구와 빈소산의 구성성분 중 유효 성분 규명을 위한 실험이 수행되어야 할 것으로 판단된다.

• Journal of Life Science
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• v.20 no.3
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• pp.388-395
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• 2010

Cyclooxygenase (COX)-2 is generally known as an inducible enzyme, and it produces arachidonic acid to prostaglandin $E_2$ ($PGE_2$), which has been demonstrated to play a critical role in inflammation. In the present study, we investigated the effects of the extracts of fermented beans including soybean (FS), black agabean (FBA) and yellow agabean (FYA), on the expression of COXs and production of $PGE_2$ in U937 human promonocytic cells. Treatment of phorbol 12-myristate 13-acetate (PMA) significantly induced pro-inflammatory mediators such as COX-2 expression and $PGE_2$ production, whereas the levels of COX-1 remained unchanged. However, pre-treatment with FS, FBA and FYA significantly decreased PMA-induced COX-2 protein as well as mRNA, which is associated with inhibition of $PGE_2$ production. Moreover, FS, FBA and FYA markedly prevented the increase of nuclear translocation of nuclear factor kappa B (NF-${\kappa}B$) p65 by PMA. Our data indicate that the extracts of fermented beans exhibits anti-inflammatory properties by suppressing the transcription of pro-inflammatory cytokine genes through the NF-${\kappa}B$ signaling pathway.

• The Korean Journal of Physiology and Pharmacology
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• v.11 no.5
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• pp.175-182
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• 2007

Members of prostaglandin(PG) E-series elicit cellular effects mainly through adenylyl cyclase-cAMP signaling. The role of $PGE_2$-induced increase in cAMP has been shown to be compartmentalized in the cardiac myocytes: $PGE_2$-induced increase of cAMP is not involved in the control of cardiomyocytic contraction. The purpose of the present study was to define the effect of $PGE_1$ on the cGMP levels and the role of $PGE_1$ in the atrial secretory function. Experiments were performed in perfused beating rabbit atria and atrial contractile responses, cGMP and cAMP efflux, and atrial natriuretic peptide(ANP) secretion were measured. $PGE_1$ increased cGMP as well as cAMP efflux concentration in a concentration-dependent manner, however, no significant changes in atrial secretory responses were observed(with $1.0{\mu}M\;PGE_1$; for cGMP, $144.76{\pm}37.5%$, n=11 versus $-16.81{\pm}4.76%$, n=6, control, p<0.01; for cAMP, $187.60{\pm}41.52%$, n=11 versus $7.38{\pm}19.44%$, n=6, control, p<0.01). $PGE_1$ decreased atrial dynamics slightly but transiently, whereas $PGE_2$ showed similar effects but with lower potency. Isoproterenol increased atrial cAMP efflux(with 2.0 nM; $145.71{\pm}41.89$, n=5 versus $7.38{\pm}19.44%$, n=6, control, p<0.05) and mechanical dynamics and decreased ANP secretion. The $PGE_1$-induced increase in cGMP efflux showed a bell-shaped concentration-response curve. $PGE_1$-induced increase of cGMP efflux was not observed in the presence of L-NAME, an inhibitor of nitric oxide(NO) synthase, or ODQ, an inhibitor of NO-sensitive guanylyl cyclase. L-NAME and ODQ showed no significant effect on the $PGE_1$-induced transient decrease of atrial dynamics. These data indicate that $PGE_1$ increases cGMP levels via NO-soluble GC signaling in the cardiac atrium and also show that $PGE_1$-induced increases in cGMP and cAMP levels are not involved in the regulation of atrial secretory and contractile functions.

• Journal of Life Science
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• v.21 no.12
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• pp.1689-1697
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• 2011

In this study, we investigated the anti-inflammation effect of Persicaria thunbergii (P. thunbergii) on RAW 264.7 murine macrophage cells. The anti-inflammatory activity of P. thunbergii was determined by measuring expression of the LPS-induced inflammatory proteins, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and nuclear factor-${\kappa}B$ (NF-${\kappa}B$), and the production of nitric oxide (NO) and prostaglandin $E_2$ ($PGE_2$). Methanol extract of P. thunbergii decreased the expression of iNOS, COX-2 and NF-${\kappa}B$, and increased the expression of HO-1 in LPS-stimulated RAW264.7 cells. Methanol extract was fractioned by n-butanol, hexane and ethyl acetate (EtOAc) and each fraction was tested for inhibitory effects on inflammation. Among the sequential solvent fractions, the EtOAc soluble fraction was investigated by the expression of prostaglandin $E_2$ ($PGE_2$), and showed decreasing form to the dose-dependent manner. EtOAc extract showed the most effective inhibitory activity of the expression of iNOS, COX-2 and NF-${\kappa}B$, and the production of NO. The study showed that P. thunbergii has anti-inflammatory activity through the decrease of NO and inhibition of iNOS, COX-2, $PGE_2$ and NF-${\kappa}B$ expression, and by the increase of HO-1 enzyme. This study needs for more investigation to find out the most effective single compound with anti-inflammatory activity.

• Journal of the Korean Society of Food Science and Nutrition
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• v.35 no.1
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• pp.28-34
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• 2006

The ethanol extracts of Puerariae Radix inhibited cyclooxygenase-2 (COX-2) activity in bone marrow derived mast cells (BMMC). COX-2 is responsible for the production of large amounts of proinflammatory prostaglandins (PGs) at the inflammatory site. We have investigated the anti-inflammatory effect of ethyl acetate fraction from $70\%$ ethanol extract of Puerariae Radix (EPR), and attempted acetic acid induced writhing to verify the analgesic effect. Inflammation was induced by interleukin-1 (IL-1), tumor necrosis factor-a (TNF-a), $inteferon-\gamma$ $(IFN-\gamma)$ and lipopolysaccharide (LPS). EPR showed strong inhibitory efficacy against cytokine-induced proteoglycan degradation, prostaglandin $E_2\;(PGE_2)$ production, nitric oxide (NO) production, and matrix-metalloproteinases (MMPs) expression in mouse macrophage and rabbit articular chondrocyte. In the writhing test, EPR $(200\~400\;mg/kg)$ exhibited a dose-dependent inhibition of writhing. The results indicate that EPR have anti-inflammatory and analgesic activities, and could be a good herbal medicine candidate for treating of osteoarthritis (OA).

• The Korean Journal of Pain
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• v.20 no.1
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• pp.15-20
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• 2007

Background: Lipo-prostaglandin E1 (Lipo-$PGE_1$) has vasodilating and platelet aggregation inhibitory characteristics and it has been used as a treatment for patients with blood flow dysfunction disease. Based on the mechanisms of lumbar spinal stenosis, including veno congestion, neuro-ischemia and mechanical compression, we aimed to study whether intravenous Lipo-$PGE_1$ injection has any therapeutic effect on hyperalgesia in a rat foraminal stenosis model. Methods: In this study, twenty male Sprague-Dawley rats were divided into the control (n = 10) and Lipo-$PGE_1$ (n = 10) groups. A small stainless steel rod was inserted into the L5-6 intervertebral foramen to induce intervertebral foramen stenosis and chronic DRG compression. In the Lipo-$PGE_1$ group, $0.15{\mu}g/kg$ of Lipo-$PGE_1$ were injected intravenously via a tail vein for 10 days starting from the $3^{rd}$ day after operation. Behavioral testing for mechanical and thermal hyperalgesia was performed for 3 weeks after the injections. Results: From the $10^{th}$ day after Lipo-$PGE_1$ injection, the rats in the experimental group showed significant recovery of their mechanical threshold, and this effect was maintained for 3 weeks. No significant differences of the thermal hyperalgesia were observed between the two groups. Conclusions: These findings suggest that intravenously injected Lipo-$PGE_1$ may be effective for alleviating neuropathic pain, which isthe main symptom of spinal stenosis, by improving the blood flow dysfunction.