BACKGROUND & AIMS: :Bile acids are synthesized in the liver and are the major component in bile. Impaired bile flow leads to cholestasis that is characterized by elevated levels of bile acid in the liver and serum, followed by hepatocyte and biliary injury. Although the causes of cholestasis have been extensively studied, the molecular mechanisms as to how bile acids initiate liver injury remain controversial. In this chapter, we summarize recent advances in the pathogenesis of bile acid induced liver injury. These include bile acid signaling pathways in hepatocytes as well as the response of cholangiocytes and innate immune cells in the liver in both patients with cholestasis and cholestatic animal models. We focus on how bile acids trigger the production of molecular mediators of neutrophil recruitment and the role of the inflammatory response in this pathological process. These advances point to a number of novel targets where drugs might be judged to be effective therapies for cholestatic liver injury.

背景与目标： 胆汁酸是在肝脏中合成的，是胆汁中的主要成分。胆汁流量受损导致胆汁淤积，其特征是肝脏和血清中胆汁酸水平升高，随后是肝细胞和胆道损伤。尽管已经对胆汁淤积的原因进行了广泛的研究，但是关于胆汁酸如何引发肝损伤的分子机制仍存在争议。在本章中，我们总结了胆汁酸引起的肝损伤的发病机理的最新进展。在胆汁淤积和胆汁淤积动物模型的患者中，这些都包括肝细胞中的胆汁酸信号通路以及肝中胆管细胞和先天免疫细胞的应答。我们专注于胆汁酸如何触发中性粒细胞募集分子介体的产生以及炎症反应在此病理过程中的作用。这些进展指出了许多新的靶点，在这些靶点中，药物可能被认为是胆汁淤积性肝损伤的有效疗法。

BACKGROUND & AIMS: Prostaglandins and thromboxanes are products of arachidonic acid metabolism via the cyclooxygenase (CO) enzyme and are responsible for the pain and swelling common to sites of inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the production of these substances and are used in the treatment of inflammatory diseases such as arthritis. However, one of the major side-effects of NSAID therapy is gastric ulceration. It is possible that inhibition of prostaglandin production and a related increase in the formation of leukotrienes via the 5-lipoxygenase (5-LO) enzymatic pathway are responsible for attracting inflammatory cells, causing local sites of inflammation and producing ulceration. To determine the effects of 5-LO inhibition on this hypothesis, studies were performed in rats to evaluate the effects of tepoxalin, a dual CO/LO inhibitor on leukotriene B4 levels in gastric mucosa and neutrophil adhesion in mesenteric venules. In rats, chronic oral administration of an NSAID, indomethacin (2 mg/kg daily over 4 days), resulted in 40% mortality, accompanied by intestinal adhesions and perforations when evaluated 24 h after the fourth dose of drug. Additionally, neutrophil adhesion was increased in the mesenteric venules and cell infiltration was evident in the mesenteric interstitium. These gastrointestinal side-effects were inhibited in a separate group of rats administered tepoxalin (20 mg/kg, p.o) 30 min prior to each daily indomethacin treatment. Further studies were performed to determine tepoxalin's effects on early events associated with NSAID-induced gastrointestinal inflammation, including neutrophil adhesion, lipid peroxide generation and LTB4 production. Indomethacin (100 mg/kg, p.o.) produced elevated levels of LTB4 in rat gastric mucosa 90 min after administration. Additionally, neutrophil adhesion in mesenteric venules was increased at this dose and with the administration of another NSAID, naproxen. No generation of lipid peroxides was evident in the gastric mucosa at this timepoint. Tepoxalin (up to 400 mg/kg, p.o.) did not have an effects on gastric mucosal LTB4 generation and lipid peroxide levels. A decrease in neutrophil adhesion was observed at the highest dose. In another study, pretreatment with tepoxalin (ED50=7.5 mg/kg, p.o.) or the selective 5-LO inhibitor zileuton (100 mg/kg, p.o.) prevented the increases in gastric mucosal LTB4 levels and neutrophil adhesion induced by indomethacin (100 mg/kg, p.o.). These data suggest that LO inhibition may play a vital role in the prevention of NSAID-induced gastric inflammation, providing insight into the lack of ulcerogenicity with tepoxalin and new approaches to anti-inflammatory therapy which may prevent gastric side effects.

背景与目标： 前列腺素和血栓烷是花生四烯酸通过环氧合酶（CO）酶代谢的产物，它们是炎症部位常见的疼痛和肿胀的原因。非甾体类抗炎药（NSAIDs）抑制这些物质的产生，并用于治疗炎症性疾病，例如关节炎。但是，NSAID治疗的主要副作用之一是胃溃疡。通过5-脂氧合酶（5-LO）酶促途径抑制前列腺素的产生以及白三烯形成的相关增加可能是吸引炎症细胞，引起炎症的局部部位和产生溃疡的原因。为了确定5-LO抑制对这一假设的影响，在大鼠中进行了研究以评估替泊沙林（一种双重CO / LO抑制剂）对胃粘膜白三烯B4水平和肠系膜小静脉中性粒细胞粘附的影响。在大鼠中，长期口服NSAID，消炎痛（2天每天2 mg / kg，共4天）可导致40％的死亡率，并在第四剂药物后24小时进行评估，并伴有肠粘连和穿孔。另外，在肠系膜小静脉中嗜中性粒细胞的粘附增加，并且在肠系膜间质中细胞浸润明显。在每天进行消炎痛治疗前30分钟，给另一组大鼠服用tepoxalin（20 mg / kg，p.o），抑制了这些胃肠道副作用。进行了进一步的研究以确定替泊沙林对与NSAID诱导的胃肠道炎症相关的早期事件的影响，包括中性粒细胞粘附，脂质过氧化物的产生和LTB4的产生。吲哚美辛（100 mg / kg，p.o.）给药90分钟后，大鼠胃黏膜中LTB4的水平升高。另外，在该剂量下并通过使用另一种NSAID萘普生，肠系膜小静脉中的中性粒细胞粘附增加。在这个时间点在胃粘膜中没有明显的脂质过氧化物的产生。 Tepoxalin（最高400 mg / kg，p.o.）对胃粘膜LTB4的产生和脂质过氧化物的水平没有影响。在最高剂量下观察到嗜中性粒细胞粘附性降低。在另一项研究中，用替泊沙林（ED50 = 7.5 mg / kg，口服）或选择性5-LO抑制剂齐留通（100 mg / kg，口服）预处理可防止由吲哚美辛（100 mg / min）引起的胃粘膜LTB4水平增加和嗜中性白细胞粘附/ kg，po）。这些数据表明，LO抑制可能在预防NSAID引起的胃部炎症中起着至关重要的作用，从而提供了对特泊沙林缺乏致溃疡性的认识，并提供了可预防胃部副作用的新的抗炎治疗方法。

BACKGROUND & AIMS: :Numerous lines of evidence support a relationship between intestinal inflammation and cancer. Therefore, much attention has recently been focused on the identification of natural compounds with anti-inflammatory activities as a strategy to suppress the early stages of colorectal cancer. Because cocoa is a rich source of bioactive compounds, the present study investigated its anti-inflammatory properties in a rat model of azoxymethane (AOM)-induced colon carcinogenesis and in TNF-α-stimulated Caco-2 cells. A total of forty male rats were fed with control or cocoa-enriched diets (12 %) during 8 weeks and injected with saline or AOM (20 mg/kg body weight) during the third and fourth week (n 10 rats/group). At the end of the experiment, colon samples were evaluated for markers of inflammation. The anti-inflammatory activity of a cocoa polyphenolic extract (10 μg/ml) was examined in TNF-α-stimulated Caco-2 cells, an in vitro model of experimentally induced intestinal inflammation. The signalling pathways involved, including NF-κB and the mitogen-activated protein kinase family such as c-Jun NH₂-terminal kinases (JNK), extracellular signal-regulated kinases and p38, were also evaluated. The results show that the cocoa-rich diet decreases the nuclear levels of NF-κB and the expression of pro-inflammatory enzymes such as cyclo-oxygenase-2 and inducible NO synthase induced by AOM in the colon. Additionally, the experiments in Caco-2 cells confirm that cocoa polyphenols effectively down-regulate the levels of inflammatory markers induced by TNF-α by inhibiting NF-κB translocation and JNK phosphorylation. We conclude that cocoa polyphenols suppress inflammation-related colon carcinogenesis and could be promising in the dietary prevention of intestinal inflammation and related cancer development.

背景与目标： ：大量证据支持肠道炎症与癌症之间的关系。因此，近来许多注意力集中在鉴定具有抗炎活性的天然化合物上，作为抑制结直肠癌早期阶段的策略。由于可可是生物活性化合物的丰富来源，因此本研究在由乙氧基甲烷（AOM）诱导的结肠癌发生的大鼠模型中以及在TNF-α刺激的Caco-2细胞中研究了其抗炎特性。总共40只雄性大鼠在8周内接受了对照或富含可可的饮食（12％），并在第三和第四周内注射了盐水或AOM（20 mg / kg体重）（每组10只大鼠）。在实验结束时，评估结肠样品的炎症标志物。在可诱导肠道炎症的体外模型TNF-α刺激的Caco-2细胞中检测了可可多酚提取物（10μg/ ml）的抗炎活性。还评估了涉及的信号通路，包括NF-κB和丝裂原活化的蛋白激酶家族，例如c-Jun NH 2末端激酶（JNK），细胞外信号调节激酶和p38。结果表明，富含可可的饮食降低了结肠中NF-κB的核水平，降低了AOM诱导的促炎性酶（如环氧化酶2和可诱导的NO合酶）的表达。此外，在Caco-2细胞中进行的实验证实，可可多酚通过抑制NF-κB易位和JNK磷酸化，有效下调TNF-α诱导的炎症标志物的水平。我们得出的结论是，可可多酚抑制炎症相关的结肠癌发生，并且在饮食预防肠道炎症和相关的癌症发展中可能很有希望。

BACKGROUND & AIMS: :Functional deficiency of the FEN1 gene has been suggested to cause genomic instability and cancer predisposition. We have identified a group of FEN1 mutations in human cancer specimens. Most of these mutations abrogated two of three nuclease activities of flap endonuclease 1 (FEN1). To demonstrate the etiological significance of these somatic mutations, we inbred a mouse line harboring the E160D mutation representing mutations identified in human cancers. Selective elimination of nuclease activities led to frequent spontaneous mutations and accumulation of incompletely digested DNA fragments in apoptotic cells. The mutant mice were predisposed to autoimmunity, chronic inflammation and cancers. The mutator phenotype results in the initiation of cancer, whereas chronic inflammation promotes the cancer progression. The current work exemplifies the approach of studying the mechanisms of individual polymorphisms and somatic mutations in cancer development, and may serve as a reference in developing new therapeutic regimens through the suppression of inflammatory responses.

背景与目标： FEN1基因的功能缺陷已被认为可导致基因组不稳定和癌症易感性。我们在人类癌症标本中鉴定出一组FEN1突变。大多数这些突变废除了皮瓣内切核酸酶1（FEN1）的三种核酸酶活性中的两种。为了证明这些体细胞突变的病因学意义，我们引入了携带E160D突变的小鼠品系，该E160D突变代表在人类癌症中鉴定出的突变。核酸酶活性的选择性消除导致凋亡细胞中频繁的自发突变和不完全消化的DNA片段的积累。突变小鼠易患自身免疫，慢性炎症和癌症。突变表型导致癌症的开始，而慢性炎症则促进癌症的发展。目前的工作例证了研究癌症发展中个体多态性和体细胞突变机制的方法，并可作为通过抑制炎症反应开发新的治疗方案的参考。

BACKGROUND & AIMS: :Oncolytic viruses (OVs) are selected or designed to eliminate malignancies by direct infection and lysis of cancer cells. In contrast to this concept of direct tumor lysis by viral infection, we observed that a significant portion of the in vivo tumor killing activity of two OVs, vesicular stomatitis virus (VSV) and vaccinia virus is caused by indirect killing of uninfected tumor cells. Shortly after administering the oncolytic virus we observed limited virus infection, coincident with a loss of blood flow to the interior of the tumor that correlated with induction of apoptosis in tumor cells. Transcript profiling of tumors showed that virus infection resulted in a dramatic transcriptional activation of pro-inflammatory genes including the neutrophil chemoattractants CXCL1 and CXCL5. Immunohistochemical examination of infected tumors revealed infiltration by neutrophils correlating with chemokine induction. Depletion of neutrophils in animals prior to VSV administration eliminated uninfected tumor cell apoptosis and permitted more extensive replication and spreading of the virus throughout the tumor. Taken all together, these results indicate that targeted recruitment of neutrophils to infected tumor beds enhances the killing of malignant cells. We propose that activation of inflammatory cells can be used for enhancing the effectiveness of oncolytic virus therapeutics, and that this approach should influence the planning of therapeutic doses.

背景与目标： 选择或设计溶瘤病毒（OVs），以通过直接感染和裂解癌细胞来消除恶性肿瘤。与通过病毒感染直接裂解肿瘤的概念相反，我们观察到两个OV（水泡性口腔炎病毒（VSV）和牛痘病毒）在体内的大部分肿瘤杀伤活性是由未杀伤的肿瘤细胞的间接杀伤引起的。在施用溶瘤病毒后不久，我们观察到有限的病毒感染，与流向肿瘤内部的血流减少相一致，这与诱导肿瘤细胞凋亡有关。肿瘤的转录谱分析表明，病毒感染导致促炎基因（包括嗜中性粒细胞趋化因子CXCL1和CXCL5）的转录激活。感染组织的免疫组织化学检查显示，嗜中性粒细胞浸润与趋化因子诱导有关。在施用VSV之前，动物中性粒细胞的消耗消除了未感染的肿瘤细胞凋亡，并允许病毒在整个肿瘤中更广泛地复制和传播。综上所述，这些结果表明嗜中性粒细胞靶向募集至感染的肿瘤床增强了对恶性细胞的杀死。我们建议炎症细胞的激活可用于增强溶瘤病毒疗法的有效性，并且这种方法应影响治疗剂量的计划。

BACKGROUND & AIMS: :Particulate matter PM2.5 is a class of airborne particles and droplets with sustained high levels in many developing countries. Epidemiological studies have shown the association between sustained high level of PM2.5 and the risk of many diseases in the respiratory system, including lung cancer. However, the precise mechanisms through which PM2.5 induces respiratory diseases are still unclear. In this study, we demonstrated that CD4+ and CD8+ T cells following PM2.5 treatment demonstrated significantly elevated mRNA and protein levels of interferon (IFN)-γ, interleukin (IL)-10, IL-17, and IL-21 production. This increase in cytokines required the presence of macrophages, such that CD4+ and CD8+ T cells treated with PM2.5 in the absence of macrophages did not present higher IFN-γ, IL-10, or IL-21 expression. In contrast, PM2.5-treated macrophages could significantly upregulate T cell cytokine secretion, even when excess PM2.5 was removed from cell culture. We also observed a macrophage-dependent upregulation of granzyme A and granzyme B expression by CD4+ and CD8+ T cells following PM2.5 treatment. These PM2.5-stimulated CD4+ and CD8+ T cells potently induced the death of human bronchial epithelial (HBE) cells. Interestingly, the CD4+ and CD8+ T cells presented synergistic effects at inducing HBE cytotoxicity, such that CD4+ T cells and CD8+ T cells combined resulted in higher HBE cell death than the sum of the separate effects of CD4+ T cells and CD8+ T cells. While blocking cytotoxic molecule release significantly compromised the T cell-mediated cytotoxicity against HBE cells, blocking IFN-γ, but not IL-10, could also slightly but significantly reduce T cell-mediated cytotoxicity. Together, these data demonstrated that PM2.5 could promote the inflammation of cytotoxicity of T cells in a macrophage-dependent manner. In addition, PM2.5-treated macrophages presented long-lasting proinflammatory effects on T cells.

背景与目标： ：颗粒物PM2.5是一类在许多发展中国家持续高水平飞行的空气颗粒和小滴。流行病学研究表明，持续高水平的PM2.5与呼吸系统多种疾病（包括肺癌）的风险之间存在关联。然而，PM2.5诱发呼吸系统疾病的确切机制仍不清楚。在这项研究中，我们证明了PM2.5治疗后的CD4和CD8 T细胞显示出干扰素（IFN）-γ，白介素（IL）-10，IL-17和IL-21产生的mRNA和蛋白质水平显着提高。细胞因子的这种增加需要巨噬细胞的存在，以致在没有巨噬细胞的情况下用PM2.5处理的CD4和CD8 T细胞不会表现出更高的IFN-γ，IL-10或IL-21表达。相反，即使从细胞培养物中去除了过量的PM2.5，经PM2.5处理的巨噬细胞也可以显着上调T细胞细胞因子的分泌。我们还观察到PM2.5处理后CD4和CD8 T细胞巨噬细胞依赖颗粒酶A和颗粒酶B表达的上调。这些PM2.5刺激的CD4和CD8 T细胞有效诱导人支气管上皮（HBE）细胞死亡。有趣的是，CD4和CD8 T细胞在诱导HBE细胞毒性方面表现出协同作用，因此与CD4 T细胞和CD8 T细胞单独作用的总和相比，CD4 T细胞和CD8 T细胞的结合导致更高的HBE细胞死亡。尽管阻断细胞毒性分子的释放显着损害了针对HBE细胞的T细胞介导的细胞毒性，但阻断IFN-γ（而非IL-10）也可以略微但显着降低T细胞介导的细胞毒性。总之，这些数据表明PM2.5可以以巨噬细胞依赖性方式促进T细胞的细胞毒性炎症。此外，经PM2.5处理的巨噬细胞对T细胞具有持久的促炎作用。

BACKGROUND & AIMS: :Multiple sclerosis (MS) is an autoimmune disease where myelin is incorrectly recognized as foreign and attacked by the adaptive immune system. Dendritic cells (DCs) direct adaptive immunity by presenting antigens to T cells, therefore serving as a target for autoimmune therapies. N-Phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxamide (PHCCC), a positive allosteric modulator of metabotropic glutamate receptor 4 (mGluR4), can promote regulatory T cells by altering cytokine secretion to bias T cell differentiation. The therapeutic potential of PHCCC, however, is hindered by dose-limiting toxicity, poor solubility, and the need for frequent dosing. We hypothesized liposomal delivery of PHCCC might enable safe, effective delivery of this hydrophobic drug to exploit metabolism as a means of controlling inflammation in self-reactive immune cells. PHCCC was readily encapsulated in liposomes modified with polyethylene glycol. Under sink conditions, controlled release resulted in 58% of drug released into media over 18 hours. Culture of primary DCs with PHCCC liposomes reduced pro-inflammatory cytokine secretion while reducing toxicity four-fold compared with soluble PHCCC. During co-culture of DCs with myelin-reactive T cells from transgenic mice, PHCCC liposomes reduced T cell proliferation and interferon gamma secretion. These results support the potential of using liposomes to promote tolerance through biocompatible delivery of metabolic modulators. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2977-2985, 2017.

背景与目标： ：多发性硬化症（MS）是一种自身免疫性疾病，其中髓磷脂被错误地识别为异物并受到适应性免疫系统的攻击。树突状细胞（DC）通过向T细胞呈递抗原来指导适应性免疫，因此可作为自身免疫疗法的靶标。 N-苯基-7-（羟基亚氨基）环丙[b]铬n-1a-羧酰胺（PHCCC）是代谢型谷氨酸受体4（mGluR4）的正变构调节剂，可通过改变细胞因子分泌来促进T细胞调节，从而偏向T细胞分化。然而，PHCCC的治疗潜力受到剂量限制的毒性，不良的溶解性以及需要频繁给药的限制。我们假设PHCCC的脂质体递送可能使这种疏水性药物安全有效地递送，从而利用新陈代谢作为控制自身反应性免疫细胞中炎症的手段。 PHCCC容易封装在用聚乙二醇修饰的脂质体中。在水槽条件下，控释导致58％的药物在18小时内释放到培养基中。与可溶性PHCCC相比，用PHCCC脂质体培养初级DC可以减少促炎性细胞因子的分泌，同时将毒性降低四倍。在DC与来自转基因小鼠的髓磷脂反应性T细胞共培养期间，PHCCC脂质体降低了T细胞增殖和干扰素γ分泌。这些结果支持使用脂质体通过代谢调节剂的生物相容性递送来提高耐受性的潜力。分级为4 +©2017 Wiley Periodicals，Inc.J Biomed Mater Res Part A：105A：2977-2985，2017。

BACKGROUND & AIMS: :Aging predisposes to hepatic dysfunction and inflammation that can contribute to the development of non-alcoholic fatty liver disease. Spirulina, a cyanobacterium used as a food additive or food supplement, has been shown to impact immune function. We have tested the potential hepatoprotective effect of a Spirulina in aged mice and to determine whether these effects can be related to a modulation of the gut microbiota. Old mice have been fed a standard diet supplemented with or without 5% Spirulina for six weeks. Among several changes of gut microbiota composition, an increase in Roseburia and Lactobacillus proportions occurs upon Spirulina treatment. Interestingly, parameters related to the innate immunity are upregulated in the small intestine of Spirulina-treated mice. Furthermore, the supplementation with Spirulina reduces several hepatic inflammatory and oxidative stress markers that are upregulated in old mice versus young mice. We conclude that the oral administration of a Spirulina is able to modulate the gut microbiota and to activate the immune system in the gut, a mechanism that may be involved in the improvement of the hepatic inflammation in aged mice. Those data open the way to new therapeutic tools in the management of immune alterations in aging, based on gut microbe-host interactions.

背景与目标： ：衰老易患肝功能障碍和炎症，可导致非酒精性脂肪肝疾病的发展。螺旋藻是一种用作食品添加剂或食品补充剂的蓝细菌，已显示会影响免疫功能。我们已经测试了螺旋藻对老年小鼠的潜在肝保护作用，并确定这些作用是否与肠道菌群的调节有关。老老鼠已经接受了补充或不加入5％螺旋藻的标准饮食，持续了六周。在肠道菌群组成的几种变化中，螺旋藻治疗后玫瑰果菌和乳杆菌的比例增加。有趣的是，在螺旋藻治疗小鼠的小肠中，与先天免疫有关的参数被上调。此外，螺旋藻的补充减少了在老年小鼠与年轻小鼠中上调的几种肝炎性和氧化应激标志物。我们得出的结论是，螺旋藻的口服给药能够调节肠道菌群并激活肠道免疫系统，该机制可能与改善老年小鼠的肝脏炎症有关。这些数据基于肠道微生物与宿主之间的相互作用，为处理衰老中的免疫变化提供了新的治疗手段。

BACKGROUND & AIMS: :The inhibitory effects of 2,3,5,4'-tetrahydroxystilbene-2-O-beta-d-glucoside (THSG), extracted from the roots of Polygonum multiflorum Thunb, on inflammatory activity in animal models and cyclooxygenase-2 (COX-2) activity in lipopolysaccharide (LPS)-induced mouse RAW264.7 macrophage cells were investigated. The carrageenin (CGN)-induced rat paw oedema model and dimethylbenzene-induced mouse ear oedema model were prepared; MTT assay, semi-quantitative RT-PCR, Western blot and ELISA were adopted. THSG 2.3, 4.6 and 9.2 mg kg(- 1) by oral administration inhibited mouse ear oedema and the percentage of inhibition of THSG 9.2 mg kg(- 1) is 87%. THSG 3.2, 6.4 and 12.8 mg kg(- 1) by oral administration dose-dependently inhibited rat paw oedema and the percentage of inhibition of THSG 12.8 mg kg(- 1) is 56% at 6 h. Indomethacin 13 and 9 mg kg(- 1) showed 90% and 57% inhibition in the same animal models, respectively. LPS 1 microg ml(- 1) significantly up-regulated prostaglandin E(2) (PGE(2)) production (inducing COX-2 activity) by 35% (exogenous arachidonic acid, AA), which was dose-dependently decreased by THSG 1, 10, and 100 micromol L(- 1) and the percentage of inhibition of THSG 10 micromol L(- 1) was 40%. NS-398 10 micromol L(- 1) decreased PGE(2) production by 42%. THSG 1, 10, 100 micromol L(- 1) was shown to markedly inhibit the LPS-induced COX-2 protein and mRNA expression in RAW264.7 cells (P < 0.05) but had no effect on COX-1 protein and mRNA (P>0.05). In summary, the data showed that THSG possessed an anti-inflammatory effect, which was perhaps related to the inhibition of COX-2 enzyme activity and expression in RAW264.7 macrophage cells.

背景与目标： ：从何首乌根中提取的2,3,5,4'-四羟基O-2-O-β-d-葡萄糖苷（THSG）对动物模型和环氧合酶2（COX）的炎性活性有抑制作用-2）研究了脂多糖（LPS）诱导的小鼠RAW264.7巨噬细胞的活性。制备了角叉菜胶（CGN）诱导的大鼠爪水肿模型和二甲基苯诱导的小鼠耳水肿模型；采用MTT法，半定量RT-PCR，Western blot和ELISA。口服THSG 2.3、4.6和9.2 mg kg（-1）抑制了小鼠耳部水肿，THSG 9.2 mg kg（-1）的抑制百分比为87％。口服THSG 3.2、6.4和12.8 mg kg（-1）剂量依赖性抑制大鼠足水肿，在6 h时THSG 12.8 mg kg（-1）的抑制百分比为56％。吲哚美辛13和9 m​​g kg（-1）在同一动物模型中分别显示90％和57％的抑制作用。 LPS 1 microg ml（-1）显着上调前列腺素E（2）（PGE（2））的产生（诱导COX-2活性）35％（外源花生四烯酸，AA），THSG剂量依赖性降低1，10和100 micromol L（-1）和THSG 10 micromol L（-1）的抑制率为40％。 NS-398 10 micromol L（-1）使PGE（2）产量降低了42％。 THSG 1、10、100 micromol L（-1）可显着抑制LPS诱导的RAW264.7细胞中COX-2蛋白和mRNA表达（P <0.05），但对COX-1蛋白和mRNA没有影响（ P> 0.05）。总之，数据显示THSG具有抗炎作用，这可能与抑制COX-2酶活性和在RAW264.7巨噬细胞中的表达有关。

BACKGROUND & AIMS: :CRH, the hypothalamic component of the hypothalamic-pituitary adrenal axis, attenuates inflammation through stimulation of glucocorticoid release, whereas peripherally expressed CRH acts as a proinflammatory mediator. CRH is expressed in the intestine and up-regulated in patients with ulcerative colitis. However, its pathophysiological significance in intestinal inflammatory diseases has just started to emerge. In a mouse model of acute, trinitrobenzene sulfonic acid-induced experimental colitis, we demonstrate that, despite low glucocorticoid levels, CRH-deficient mice develop substantially reduced local inflammatory responses. These effects were shown by histological scoring of tissue damage and neutrophil infiltration. At the same time, CRH deficiency was found to be associated with higher serum leptin and IL-6 levels along with sustained anorexia and weight loss, although central CRH has been reported to be a strong appetite suppressor. Taken together, our results support an important proinflammatory role for CRH during mouse experimental colitis and possibly in inflammatory bowel disease in humans. Moreover, the results suggest that CRH is involved in homeostatic pathways that link inflammation and metabolism.

背景与目标： ：CRH，下丘脑-垂体肾上腺轴的下丘脑成分，通过刺激糖皮质激素释放来减轻炎症，而外周表达的CRH则充当促炎介质。 CRH在溃疡性结肠炎患者的肠中表达并上调。然而，其在肠道炎性疾病中的病理生理意义才刚刚开始显现。在急性三硝基苯磺酸诱导的实验性结肠炎的小鼠模型中，我们证明，尽管糖皮质激素水平较低，但CRH缺陷型小鼠的局部炎症反应却大大降低。组织损伤和中性粒细胞浸润的组织学评分显示了这些作用。同时，CRH缺乏症与血清瘦素和IL-6水平升高以及持续的厌食和体重减轻有关，尽管据报道中枢性CRH是强烈的食欲抑制剂。两者合计，我们的结果支持在小鼠实验性结肠炎期间CRH的重要促炎作用，并可能在人类的炎症性肠病中。此外，结果表明CRH参与了连接炎症和新陈代谢的体内平衡途径。

BACKGROUND & AIMS: :The Brucella genus is able to cause chronic infection in a wide range of mammals including humans. Oxidative events, lipid peroxidation and inflammatory response against Brucella infection have not yet been well elucidated in vivo. We have investigated oxidative/antioxidative status and nitric oxide production in plasma, brain, liver and spleen during a 60 day period of B. melitensis infection in a rat model. In addition, inducible nitric oxide synthase (iNOS), IL-10, IL-12, IFN-gamma and TNF-alpha mRNA transcriptions were analyzed by semiquantitative reverse transcriptase PCR (RT-PCR) in brain samples. Animals were infected with B. melitensis and sacrificed at 7th, 15th, 30th, 45th and 60th day of post-inoculation. Malondialdehyde (MDA), as an indicator of lipid peroxidation, and nitric oxide (NO) concentrations were significantly increased after Brucella inoculation and began to decline to basal levels from 45th day in plasma, liver and spleen. However, iNOS transcription was not induced during the infection period in brains. In contrast, MDA level was increased in brain during the late phase of infection without any change in NO production. The infection did not alter the antioxidant enzyme activities in the tissues; although significantly increased catalase activity was observed between days 30 and 45 in the liver. Transcription analyses demonstrated that IL-10, IL-12 and IFN-gamma mRNA level were not induced in the brain. Only TNF-alpha mRNA was weakly up-regulated in brain 30 days after pathogen inoculation. The results obtained in this study demonstrate that B. melitensis induces lipid peroxidation and NO production in the liver and spleen in the early days of infection, but that these levels subsequently decline. Moreover, Brucella does not appear to induce antioxidant enzyme activities and inflammation during two months of infection. However, the pathogen does stimulate cerebral lipid peroxidation in the late phase of infection without causing significant inflammation.

背景与目标： 布鲁氏菌属能够在包括人类在内的多种哺乳动物中引起慢性感染。体内尚未充分阐明针对布鲁氏菌感染的氧化事件，脂质过氧化作用和炎症反应。我们在大鼠模型中调查了B. melitensis感染60天期间血浆，脑，肝脏和脾脏的氧化/抗氧化状态和一氧化氮的产生。此外，通过半定量逆转录酶PCR（RT-PCR）分析了脑样本中的诱导型一氧化氮合酶（iNOS），IL-10，IL-12，IFN-γ和TNF-αmRNA的转录。在接种后第7、15、30、45和60天，将动物感染了B. melitensis，并处死了动物。布鲁氏菌接种后，丙二醛（MDA）作为脂质过氧化的指标，而一氧化氮（NO）的浓度显着增加，并从第45天开始在血浆，肝脏和脾脏中降至基础水平。但是，iNOS转录在脑部感染期间没有被诱导。相反，在感染后期，大脑中的MDA水平升高，而NO产生没有任何变化。感染并没有改变组织中的抗氧化酶活性。尽管在肝脏第30至45天之间观察到过氧化氢酶活性显着增加。转录分析表明，在大脑中未诱导IL-10，IL-12和IFN-γmRNA的水平。病原菌接种后30天，仅TNF-αmRNA在大脑中微弱上调。在这项研究中获得的结果表明，肉毒梭菌在感染的早期会诱导肝脏和脾脏中脂质过氧化和NO的产生，但是这些水平随后会下降。而且，布鲁氏菌在感染两个月期间似乎没有诱导抗氧化酶活性和炎症。但是，病原体确实会在感染后期刺激脑脂质过氧化，而不会引起明显的炎症。

BACKGROUND & AIMS: :Epidemiological studies have shown that exposure to air pollution particles is associated with cardiovascular diseases, whereas the role in the initiation of atherosclerosis is unresolved. Atherosclerosis is considered to be an inflammatory disease that also involves oxidative stress. Here we investigated effects of oxidative stress elicited by diesel exhaust particles (DEP) in the aorta, liver, and lung of dyslipidemic ApoE(-/-) mice at the age when visual plaques appear in the aorta (11-13 weeks). DEP was administrated by intraperitoneal injection (0, 50, 500 and 5,000 microg DEP/kg bodyweight) in order to omit vascular effects secondary to pulmonary inflammation. The mice were killed either 6 or 24h after the administration. Inflammation was measured as the expression of inducible nitric oxide synthase (iNOS) and serum nitric oxide and DNA damage was measured by the comet assay. The expression of iNOS mRNA was increased in the liver 6h after the administration. The level of oxidized purine bases, determined as formamidopyrimidine DNA glycosylase sites was increased by 67% (95% CI: 11-124%) in the liver after 24h in the mice administrated with only 50 microg/kg bodyweight. However, there was no indication of systemic inflammation determined as the serum concentration of nitric oxide and iNOS expression, and DNA damage was not increased in the aorta. These observations indicate that intraperitoneal DEP injection does not induce inflammation or oxidatively damaged DNA in the lung and aorta, whereas a direct effect in terms of inflammation and oxidized DNA was observed in the liver of dyslipidemic ApoE(-/-) mice.

背景与目标： ：流行病学研究表明，暴露于空气污染颗粒与心血管疾病有关，而在引发动脉粥样硬化中的作用尚无定论。动脉粥样硬化被认为​​是还涉及氧化应激的炎性疾病。在这里，我们研究了血脂异常ApoE（-/-）小鼠在主动脉出现斑块的年龄（11-13周）时，柴油机排气颗粒（DEP）在主动脉，肝脏和肺中引起的氧化应激的影响。通过腹膜内注射给予DEP（0、50、500和5,000 microg DEP / kg体重），以消除继发于肺部炎症的血管作用。给药后6或24小时处死小鼠。通过诱导型一氧化氮合酶（iNOS）和血清一氧化氮的表达来测量炎症，并通过彗星试验测量DNA损伤。给药6h后，肝脏中iNOS mRNA的表达增加。仅以50 microg / kg体重给药的小鼠在24小时后，肝脏中被氧化的嘌呤碱基水平（被确定为甲酰嘧啶DNA糖基化酶位点）增加了67％（95％CI：11-124％）。然而，没有根据血清一氧化氮浓度和iNOS表达确定全身炎症的迹象，主动脉中的DNA损伤也没有增加。这些观察结果表明，腹膜内DEP注射不会在肺和主动脉中引起炎症或氧化损伤的DNA，而在血脂异常的ApoE（-/-）小鼠的肝脏中观察到了对炎症和氧化的DNA的直接作用。

BACKGROUND & AIMS: :Excessive uptake of fatty acids and glucose by adipose tissue triggers adipocyte dysfunction and infiltration of immune cells. Altered metabolic homeostasis in adipose tissue promotes insulin resistance, type 2 diabetes, hypertension, and cardiovascular disease. Inflammatory and metabolic processes are mediated by certain proteolytic enzymes that share a common cellular target, protease-activated receptor 2 (PAR2). This study showed that human and rat obesity correlated in vivo with increased expression of PAR2 in adipose tissue, primarily in stromal vascular cells (SVCs) including macrophages. PAR2 was expressed more than other PARs on human macrophages and was increased by dietary fatty acids (palmitic, stearic, and myristic). A novel PAR2 antagonist, GB88 (5-isoxazoyl-Cha-Ile-spiroindene-1,4-piperidine), given orally at 10 mg/kg/d (wk 8-16) reduced body weight by ∼10% in obese rats fed a high-carbohydrate high-fat (HCHF) diet for 16 wk, and strongly attenuated adiposity, adipose tissue inflammation, infiltrated macrophages and mast cells, insulin resistance, and cardiac fibrosis and remodeling; while reversing liver and pancreatic dysfunction and normalizing secretion of PAR2-directed glucose-stimulated insulin secretion in MIN6 β cells. In summary, PAR2 is a new biomarker for obesity, and its expression is stimulated by dietary fatty acids; PAR2 is a substantial contributor to inflammatory and metabolic dysfunction; and a PAR2 antagonist inhibits diet-induced obesity and inflammatory, metabolic, and cardiovascular dysfunction.

背景与目标： ：脂肪组织摄入过多的脂肪酸和葡萄糖会触发脂肪细胞功能障碍和免疫细胞浸润。脂肪组织中代谢稳态的改变会促进胰岛素抵抗，2型糖尿病，高血压和心血管疾病。炎症和代谢过程由共享共同细胞靶标，蛋白酶激活受体2（PAR2）的某些蛋白水解酶介导。这项研究表明，人和大鼠的肥胖症在体内与PAR2在脂肪组织（主要是在包括巨噬细胞的基质血管细胞（SVC））中表达的增加有关。 PAR2在人类巨噬细胞上的表达高于其他PAR，并且通过膳食脂肪酸（棕榈酸，硬脂酸和肉豆蔻酸）增加。以10 mg / kg / d（wk 8-16）口服给予的新型PAR2拮抗剂GB88（5-isoxazoyl-Cha-Ile-spirindindene-1,4-piperidine）在体重减轻的肥胖大鼠中体重减轻了约10％ 16周的高碳水化合物高脂（HCHF）饮食，可大大减轻肥胖，脂肪组织炎症，巨噬细胞和肥大细胞浸润，胰岛素抵抗以及心脏纤维化和重塑。同时逆转肝和胰腺功能障碍，并使MIN6β细胞中PAR2指导的葡萄糖刺激的胰岛素分泌正常化。总之，PAR2是肥胖的一种新的生物标志物，它的表达受到饮食脂肪酸的刺激。 PAR2是导致炎症和代谢功能障碍的重要因素。 PAR2拮抗剂可抑制饮食引起的肥胖症以及炎症，代谢和心血管功能障碍。

BACKGROUND & AIMS: :The effect of leptin on ulcerative colitis (UC) has been controversial. The present study aimed to investigate the role of leptin and its receptor ob‑R in UC and the underlying mechanism of this role. The level of serum leptin and the protein expression of the leptin receptor ob‑R in the colonic mucosa were determined in patients with UC. Experimental colitis was induced through intrarectal administration of 2,4,6‑trinitrobenzene sulfonic acid (TNBS) in leptin receptor‑deficient Zucker rats (LR‑D). The body weight, disease activity index, colon length, and macroscopic and histopathological appearance were evaluated. Furthermore, the myeloperoxidase (MPO) enzyme activity and cytokine levels in colon tissues were also determined. The expression of the signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3 (p‑STAT3), nuclear factor (NF)‑κB‑p65, and Ras homolog gene family member A (RhoA) proteins in colon tissues was assessed. The results revealed that the expression of the leptin receptor ob‑R was increased in the colonic mucosa but the serum leptin level was not altered in patients with UC compared with healthy volunteers. The severity of experimental colitis, represented by body weight loss, disease activity index, colon length, and macroscopic and histological changes, was ameliorated in LR‑D rats compared with the wild‑type (WT) rats. Moreover, the MPO activity; levels of cytokines including interleukin (IL)‑1β, IL‑6, and tumor necrosis factor‑α; and expression of p‑STAT3, NF‑κB, and RhoA proteins were reduced in colon tissues of LR‑D rats compared with WT rats. In conclusion, activation of the leptin receptor ob‑R is an important pathogenic mechanism of UC, and leptin receptor deficiency may provide resistance against TNBS‑induced colitis by inhibiting the NF‑κB and RhoA signaling pathways.

背景与目标： 瘦素对溃疡性结肠炎（UC）的作用一直存在争议。本研究旨在研究瘦蛋白及其受体ob-R在UC中的作用以及这种作用的潜在机制。测定UC患者结肠黏膜的血清瘦素水平和瘦素受体ob‑R的蛋白表达。实验性结肠炎是通过在瘦素受体缺陷型祖克大鼠（LR‑D）中直肠内施用2,4,6-三硝基苯磺酸（TNBS）引起的。评估体重，疾病活动指数，结肠长度以及肉眼和组织病理学外观。此外，还确定了结肠组织中的髓过氧化物酶（MPO）酶活性和细胞因子水平。评估了结肠组织中信号转导和转录激活因子3（STAT3），磷酸化STAT3（p‑STAT3），核因子（NF）‑κB‑p65和Ras同源基因家族成员A（RhoA）蛋白的表达。结果表明，与健康志愿者相比，UC患者的瘦素受体ob-R的表达在结肠粘膜中增加，但血清瘦素水平没有改变。与野生型（WT）大鼠相比，LR‑D大鼠的实验性结肠炎的严重程度得到了改善，其严重程度由体重减轻，疾病活动指数，结肠长度以及宏观和组织学变化表示。此外，MPO活性；细胞因子水平，包括白介素（IL）-1β，IL-6和肿瘤坏死因子-α；与野生型大鼠相比，LR-D大鼠结肠组织中p-STAT3，NF-κB和RhoA蛋白的表达降低。总之，瘦素受体ob-R的激活是UC的重要致病机制，瘦素受体的缺乏可能通过抑制NF-κB和RhoA信号通路来提供对TNBS诱导的结肠炎的抵抗力。

BACKGROUND & AIMS: OBJECTIVE:To investigate the association of spinal inflammation on MRI in patients with various clinical, functional and radiological outcomes in patients with axial spondyloarthritis (SpA). METHODS:Three hundred and ninety-seven participants with axial SpA and back pain were recruited from 10 rheumatology centres. Clinical, biochemical and radiological parameters were collected and participants underwent MRI of the spine. MRI features including inflammatory lesions of facet joints and costovertebral joints, corner inflammatory lesions, and spondylitis were assessed. BASFI, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Global Index, BASMI and modified Stoke Ankylosing Spondylitis Spinal Score were measured. Multivariate linear regression models were used to determine the associations between MRI parameters and various clinical, functional and radiological outcomes. RESULTS:BASMI and BASFI correlated well with inflammatory features in spinal MRI. Multivariate analysis showed that lumbar facet joint inflammation was independently associated with BASMI (regression coefficient (β) = 0.12, P < 0.001), lumbar spinal flexion (β = 0.13, P = 0.00), lateral spinal flexion (β = 0.09, P = 0.04), tragus-to-wall distance (β = 0.16, P < 0.001) and BASFI (β = 0.14, P = 0.01). Costovertebral joint inflammation was also associated with BASMI (β = 0.08, P = 0.05). CONCLUSION:Inflammatory lesions of facet and costovertebral joints in MRI are associated with restriction in spinal mobility and functional impairment. These important yet commonly overlooked lesions should be reviewed in clinical practice in patients with SpA.

背景与目标： 目的：探讨脊柱炎（SpA）患者在各种临床，功能和影像学检查结果中，脊髓炎症与MRI的相关性。
方法：从10个风湿病学中心招募了379名患有轴向SpA和背痛的参与者。收集临床，生化和放射学参数，并对参与者进行脊柱MRI检查。评估了MRI特征，包括小关节和肋骨关节的炎性病变，角部炎性病变和脊柱炎。测量了BASFI，巴斯强直性脊柱炎疾病活动指数，巴斯强直性脊柱炎整体指数，BASMI和改良的斯托克强直性脊柱炎脊柱评分。多元线性回归模型用于确定MRI参数与各种临床，功能和放射学结果之间的关联。
结果：BASMI和BASFI与脊髓MRI的炎症特征密切相关。多因素分析表明，腰椎小关节炎症与BASMI（回归系数（β）= 0.12，P <0.001），腰椎屈曲（β= 0.13，P = 0.00），脊柱外侧屈曲（β= 0.09，P = 0.04），耳屏距离（β== 0.16，P << 0.001）和BASFI（β== 0.14，P4 = 0.01）。肋椎关节炎也与BASMI有关（β= 0.08，P = 0.05）。
结论：MRI小平面和肋骨关节的炎性病变与脊柱活动受限和功能障碍有关。这些重要但通常被忽视的病变应在SpA患者的临床实践中进行回顾。