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首页> 外文OA文献 >Elucidation of anti-inflammatory constituents in Hypericum perforatum extracts and delineation of mechanisms of anti-inflammatory activity in RAW 264.7 mouse macrophages
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Elucidation of anti-inflammatory constituents in Hypericum perforatum extracts and delineation of mechanisms of anti-inflammatory activity in RAW 264.7 mouse macrophages

机译：贯叶连翘提取物中抗炎成分的阐明和RAW 264.7小鼠巨噬细胞中抗炎活性机制的描述

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摘要

Hypericum perforatum (Hp) is commonly known for its anti-viral, anti-depressant, and anti-proliferative properties, but traditionally Hp was also used to treat inflammation. Studies on the anti-inflammatory activity of Hp are far less advanced than studies on other bioactivities. In fact until recently, there was still debate as to which constituents present in Hp may be responsible for the anti-inflammatory properties.;In this study, the anti-inflammatory activity and cytotoxicity of different Hp extractions and accessions and constituents present within Hp extracts were characterized in RAW 264.7 mouse macrophage cells. In contrast to the light-dependent anti-viral activity of Hp, the anti-inflammatory activity observed with all Hp extracts was light-independent. Extracts made from Hp Elixir(TM) plant material using Soxhlet ethanol or chloroform for extraction displayed superior activity to extracts made from other accessions. When pure constituents were tested, the flavonoids quercetin, quercitrin, isoquercitrin, and hyperoside, the bi-flavonoid amentoflavone, the phloroglucinol hyperforin, and light-activated naphthodianthrone pseudohypericin displayed significant reduction in lipopolysaccharide (LPS)-induced prostaglandin E2 (PGE2) production, albeit at concentrations generally higher than the amount present in the Hp extracts. Constituents that were present in the Hp extracts at concentrations close to those that inhibited the production of PGE2 were pseudohypericin and hyperforin, suggesting that they are the primary anti-inflammatory constituents along with the flavonoids, and perhaps the interactions of these constituents and other unidentified compounds are important for the anti-inflammatory activity of the Hp extracts.;To further delineate the constituents that may be important for anti-inflammatory activity, an ethanol extract of Hp was fractionated with the guidance of an anti-inflammatory bioassay, LPS-induced PGE2 production, through 4 rounds of fractionation. Four constituents were identified as putative bioactive constituents for the reduction in PGE2. When combined together at concentrations detected in the third round Hp fraction to make a 4 component system, these constituents (0.2 muM chlorogenic acid, 0.08 muM amentoflavone, 0.07 muM quercetin, and 0.03 muM pseudohypericin) explained the majority of the activity of the fraction when activated by light, but only partially explained the activity of this Hp fraction in dark conditions. One of the constituents, light-activated pseudohypericin, was necessary, but not sufficient to explain the reduction in LPS-induced PGE2 of the 4 component system. The Hp fraction and the 4 component system inhibited cyclooxygenase (COX-2) and cytosolic phospholipase A2 (cPLA2), two enzymes in the PGE2-mediated inflammatory response, in a similar way.;To further explore the potential of the four putative bioactive constituents combined into a 4 component system, we used microarray gene expression analysis to identify key gene targets of the 4 component system and the Hp fraction, a third round subfraction from an Hp ethanol extract. Twelve genes were implicated in the activity of the 4 component system +LPS and the fraction +LPS and 8 of the 12 were part of either the janus kinase and signal transducer and activator of transcription (JAK-STAT) or eicosanoid biosynthesis pathways. Additionally, these two pathways, which are important in inflammation, could be linked via the mitogen-activated protein kinase (MAPK) pathways. The 4 component system explained some of the activity of the fraction through inflammatory pathways, however; the fraction also affected genes that the 4 component system did not affect. Thus, other known or unknown compounds in the fraction may be responsible for activities that were identified in the microarray analysis, such as effects on cell cycle.
机译：贯叶连翘（Hp）因其抗病毒，抗抑郁和抗增殖特性而广为人知，但传统上，Hp也被用于治疗炎症。对Hp抗炎活性的研究远不如对其他生物活性的研究先进。实际上直到最近，关于Hp中存在的哪些成分可能与抗炎特性有关仍存在争议;在这项研究中，不同的Hp提取物以及Hp提取物中存在的种质和成分的抗炎活性和细胞毒性在RAW 264.7小鼠巨噬细胞中进行了表征。与Hp的光依赖性抗病毒活性相反，所有Hp提取物观察到的抗炎活性均与光无关。使用索氏提取乙醇或氯仿从Hp Elixir™植物材料制得的提取物表现出优于其他种质的提取物的活性。当测试纯成分时，类黄酮槲皮素，槲皮素，异槲皮苷和高丝甙，双黄酮类黄酮，间苯三酚高forin和光活化萘蒽酮假高丝素显示出脂多糖（LPS）诱导的前列腺素E2的显着减少。尽管其浓度通常高于Hp提取物中的含量。 Hp提取物中存在的浓度接近抑制PGE2产生的成分是假高丝菌素和Hyperforin，这表明它们是黄酮类的主要抗炎成分，可能是这些成分与其他未鉴定化合物的相互作用对Hp提取物的抗炎活性很重要。；为进一步描述对抗炎活性可能重要的成分，在抗炎生物测定法LPS诱导的PGE2的指导下，对Hp乙醇提取物进行了分级分离。生产，通过4轮分级分离。四个成分被确定为PGE2减少的假定生物活性成分。当在第三轮Hp馏分中检测到的浓度组合在一起以形成4组分系统时，这些成分（0.2μM绿原酸，0.08μM氢黄酮，0.07μM槲皮素和0.03μM假高丝菌素）解释了馏分的大部分活性。由光激活，但仅部分解释了该Hp组分在黑暗条件下的活性。成分之一是光激活的伪高丝菌素是必需的，但不足以解释LPS诱导的4组分系统的PGE2减少。 Hp组分和4组分系统以相似的方式抑制PGE2介导的炎症反应中的两种酶环氧合酶（COX-2）和胞质磷脂酶A2（cPLA2）。进一步研究这四种假定的生物活性成分的潜力结合到4组分系统中，我们使用微阵列基因表达分析来确定4组分系统和Hp组分（Hp乙醇提取物中的第三轮亚组分）的关键基因靶标。 12个基因与4组分系统+ LPS的活性有关，12个组分中的+ LPS和8个是janus激酶，信号转导和转录激活因子（JAK-STAT）或类花生酸生物合成途径的一部分。此外，这两个在炎症中很重要的途径可以通过有丝分裂原激活的蛋白激酶（MAPK）途径进行链接。 4组分系统通过炎症途径解释了该级分的某些活性。该部分还影响了4组分系统不影响的基因。因此，级分中的其他已知或未知化合物可能与微阵列分析中确定的活性有关，例如对细胞周期的影响。

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