Sparstolonin B as a TLR antagonist in suppression of liver inflammation through e

非酒精性脂肪性肝病(NAFLD)已成为慢性肝病最常见的形式之一 世界范围内的主要死因。它是肥胖引起的代谢综合征的关键组成部分。 从单纯性脂肪变性到NASH的转变是从良性端向恶性端进化的关键一步 光谱中的一部分。一种“二次打击”模型表明，在第一次受到肝脏脂肪变性和胰岛素抵抗的打击后， 发展纳什需要第二次打击。第二个打击主要来自肠道和脂肪组织，包括 脂多糖(LPS)、促炎性脂肪因子和毒性脂质，导致肝脏炎症。阻止 二次打击引起的肝脏炎症是防止单纯性脂肪变性向NASH转变的关键 进一步发展为肝硬变和肝细胞癌。Toll样受体(Toll-like Receptor，TLRs)，尤其是TLR2和TLR4，在Toll样受体(Toll-like Receptor，TLRs)中起关键作用。 简单的脂肪变性到NASH的转变。肝脏中脂质堆积导致肝细胞损伤并上调TLR 在多种细胞类型中表达，特别是TLR4和TLR2，进一步使这些细胞对以下配体敏感 肠源性内毒素。这会触发肝脏的炎症级联反应。因此，没有有效的治疗方法 被批准用于临床，阻断肝脏中的TLR2和TLR4信号被认为是一种有前途的策略 以阻止简单的脂肪变性到NASH的转变。最近，我们分离并鉴定了一种新的单细胞 从中草药三棱中分离得到一种有效成分--玄参素B(SsnB)，并对其活性进行了测定。 发现SSNB是一种选择性的TLR2和TLR4拮抗剂，它通过破坏TIRAP-MyD88起作用 互动。我们最近的初步研究进一步表明，SSNB降低了两只小鼠的NASH指标 模型，并调节肝脏中几个microRNAs的表达，这些microRNAs已经证明在 纳什。我们的中心假设是SSNB可以阻止从单纯性肝脂肪变性到 NASH通过抑制TLR2和TLR4信号在多种类型的肝细胞中参与 表观遗传途径。为了验证这一中心假设，我们提出了三个目标。SA1.考察……的影响 SSNB对几种小鼠模型中单纯性肝脏脂肪变性向NASH转变的影响。在这些模型中，内毒素、细胞色素P4502 底物或饮食的相互作用是NASH发展的第二大热门。SA2.来检验这一假设 SSNB通过阻断包括肝脏在内的多种细胞类型中的TLR2和TLR4信号来减弱NASH 实质细胞、间充质细胞和造血细胞。我们还将在体内确定内毒素的作用 从肠漏作为NASH炎症和进展的主要原因，并检查 SSNB关于漏气的肠子。SA3.为了阐明SSNB调控miR155表达的机制， MiR34a、miR21和miR122及其相关的下游事件，这些下游事件参与了肺炎的发病机制。 纳什。上述研究对了解SSNB在体内的作用方式具有重要意义。 抑制炎症，为将SSNB或其类似物开发成新的治疗方法铺平道路 非酒精性脂肪肝/非酒精性脂肪肝及其他相关炎症性疾病。

Non-alcoholic fatty liver disease (NAFLD) has become the most common form of chronic liver disease and one of leading causes of death worldwide. It is a key component of metabolic syndrome which results from obesity. The transition from simple steatosis to NASH is a crucial step in the evolution from the benign to malignant end of the spectrum. A "two-hit" model suggests that after a first hit by hepatic steatosis and insulin resistance, a second hit is needed to develop NASH. The second hit is mostly derived from gut and adipose tissue, including lipopolysaccharide (LPS), proinflammatory adipokines and toxic lipids, leading to liver inflammation. Blocking inflammation of liver due to the second hit is critical to preventing the transition from simple steatosis to NASH and further to cirrhosis and HCC. Toll-like receptors (TLRs), especially TLR2 and TLR4, have a key role in the simple steatosis-to-NASH transition. Lipid accumulation in liver causes liver cell injury and up-regulates TLR expression, especially TLR4 and TLR2 in multiple cell types, further sensitizing these cells to ligands such as gut-derived LPS. This triggers the inflammatory cascade in the liver. Therefore, with no effective therapies approved for clinical use, blocking TLR2 and TLR4 signaling in the liver is considered as a promising strategy to halt the simple steatosis-to-NASH transition. Recently we isolated and characterized a novel single compound, Sparstolonin B (SsnB), from a Chinese herb, Sparganium stoloniferum, and made an exciting discovery that SsnB is a selective TLR2 and TLR4 antagonist, which acts via disruption of TIRAP-MyD88 interaction. Our recent preliminary studies further showed that SsnB diminished NASH indicators in two mouse models, and modulated the expression of several microRNAs in the liver, which have demonstrated roles in NASH. Our central hypothesis is that SsnB can halt the transition from simple hepatic steatosis to NASH by virtue of its inhibition of TLR2 and TLR4 signaling in multiple liver cell types involving epigenetic pathways. To test this central hypothesis, we propose three aims. SA1. To examine the effects of SsnB on simple hepatic steatosis-to-NASH transition in several mouse models. In these models, LPS, CYP2E1 substrate or dietary interactions serve as the second hit for NASH development. SA2. To test the hypothesis that SsnB attenuates NASH by blocking TLR2 and TLR4 signaling in multiple cell types, including liver parenchymal cells, mesenchymal and hematopoietic cells. We will also establish in vivo the role of endotoxin from the leaky gut as the principle cause of inflammation and progression in NASH and examine the effects of SsnB on leaky gut. SA3. To elucidate the mechanisms by which SsnB modulates the expression of miR155, miR34a, miR21 and miR122 and the correlated downstream events that contribute to the pathogenesis of NASH. The studies designed above are highly significant in understanding the mode of action of SsnB in suppressing inflammation, paving ways for developing SsnB or its analogs into novel therapies for NAFLD/NASH and other related inflammatory diseases.