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。

BACKGROUND & AIMS: :Rhinovirus infection results in increased release of inflammatory mediators from airway epithelial cells in asthma. As an antioxidant, lycopene offers protection from adverse effects of inflammation. The aim of this study was to find an appropriate method of lycopene enrichment of airway epithelial cells and to determine the effects of lycopene enrichment on the inflammatory response of cells infected by rhinovirus or exposed to lipopolysaccharide. Lycopene enrichment of airway epithelial cells using solubilisation in tetrahydrofuran versus incorporation in liposomes was compared. After determining that solubilisation of lycopene in tetrahydrofuran was the most suitable method of lycopene supplementation, airway epithelial cells (Calu-3) were incubated with lycopene (dissolved in tetrahydrofuran) for 24 h, followed by rhinovirus infection or lipopolysaccharide exposure for 48 h. The release of interleukin-6, interleukin-8 and interferon-gamma induced protein-10 (IP-10) and their messenger RNA levels were measured using enzyme linked immunosorbent assay and reverse transcription polymerase chain reaction, respectively. Viral replication was measured by tissue culture infective dose of 50% assay. Lycopene concentration of cells and media were analysed using high-performance liquid chromatography. Preincubation of airway epithelial cells with lycopene (dissolved in tetrahydrofuran) delivered lycopene into the cells and resulted in a 24% reduction in interleukin-6 after rhinovirus-1B infection, 31% reduction in IP-10 after rhinovirus-43 infection and 85% reduction in rhinovirus-1B replication. Lycopene also decreased the release of IL-6 and IP-10 following exposure to lipopolysaccharide. We conclude that lycopene has a potential role in suppressing rhinovirus induced airway inflammation.

背景与目标： 鼻病毒感染导致哮喘中气道上皮细胞炎症介质的释放增加。番茄红素作为一种抗氧化剂，可以保护免受炎症的不良影响。这项研究的目的是找到一种合适的富集气道上皮细胞的番茄红素的方法，并确定富集番茄红素对鼻病毒感染或暴露于脂多糖的细胞的炎症反应的影响。比较了在四氢呋喃中的增溶与掺入脂质体中的番茄红素对气道上皮细胞的富集。确定番茄红素在四氢呋喃中的增溶是最合适的番茄红素补充方法后，将气道上皮细胞（Calu-3）与番茄红素（溶于四氢呋喃中）孵育24小时，然后鼻病毒感染或脂多糖暴露48小时。使用酶联免疫吸附法和逆转录聚合酶链反应分别测量白介素6，白介素8和干扰素-γ诱导的蛋白10（IP-10）的释放及其信使RNA水平。通过50％组织培养物感染剂量测定病毒复制。使用高效液相色谱法分析细胞和培养基中番茄红素的浓度。用番茄红素（溶解于四氢呋喃中）对气道上皮细胞进行预温育，将番茄红素递送到细胞中，导致在鼻病毒1B感染后白细胞介素6减少24％，在鼻病毒43感染后IP-10减少31％，减少85％在鼻病毒1B复制中。番茄红素还降低了脂多糖暴露后IL-6和IP-10的释放。我们得出结论，番茄红素在抑制鼻病毒引起的气道炎症中具有潜在作用。

BACKGROUND & AIMS: :Carpesium macrocephalum (CM) Fr. et Sav. (Compositae) has been used in Chinese folk medicine as an analgesic, hemostatic, antipyretic, and to suppress inflammatory conditions. In the present study we aimed to provide scientific evidence for the anti-inflammatory properties of CM extract and evaluate the intrinsic mechanisms involved in both in vitro and in vivo experimental models. In in vitro findings, CM significantly inhibited the LPS-stimulated release of proinflammatory mediators such as nitric oxide, tumor necrosis factor-alpha, prostaglandin E2, and interleukin-6 in RAW264.7 macrophages in a concentration-dependent fashion. The attenuation of inflammatory responses in LPS-activated RAW264.7 cells by CM was closely associated with the suppression of nuclear factor-kappa B (NF-κB) phosphorylation, IκB-α degradation, and phosphorylation of Akt. CM treatment also attenuated the phosphorylation of STAT through TRIF dependent pathways in LPS-activated RAW264.7 cells. In vivo studies revealed that CM extract concentration dependently suppressed the acetic acid-induced vascular permeability in mice. Considering the data obtained regulation of multiple signaling mechanisms involving TRIF and Akt/NF-κB pathways might be responsible for the potent anti-inflammatory action of CM, substantiating its traditional use in inflammatory diseases.

背景与目标： ：大头翁（CM）Fr.等（菊科）在中国民间医学中已用作止痛，止血，解热和抑制炎性疾病的药物。在本研究中，我们旨在为CM提取物的抗炎特性提供科学依据，并评估涉及体内和体外实验模型的内在机制。在体外研究中，CM以浓度依赖性方式显着抑制LP26刺激的RAW264.7巨噬细胞中促炎性介质（如一氧化氮，肿瘤坏死因子-α，前列腺素E2和白介素6）的LPS刺激释放。 CM在LPS激活的RAW264.7细胞中减轻炎症反应与抑制核因子-κB（NF-κB）磷酸化，IκB-α降解和Akt磷酸化密切相关。 CM处理还通过LPS激活的RAW264.7细胞中的TRIF依赖性途径减弱了STAT的磷酸化。体内研究表明，CM提取物的浓度可依赖性地抑制乙酸诱导的小鼠血管通透性。考虑到所获得的数据，涉及TRIF和Akt /NF-κB途径的多种信号传导机制的调控可能是CM强大的抗炎作用，从而证实了其在炎性疾病中的传统用途。

BACKGROUND & AIMS: BACKGROUND:HIV-infection is characterized by chronic immune activation that persists despite effective antiretroviral therapy (ART) and is associated with elevated cardiovascular risk. Whether specific perivascular fat depots are associated with inflammation in HIV is unknown. METHODS:In a cross-sectional study, epicardial (EAT) and thoracic periaortic (TAT) adipose tissue volumes were measured by computed tomography in 100 HIV-infected adults, on stable ART, with LDL-cholesterol ≤130 mg/dL and evidence of heightened T-cell activation (CD8+CD38+HLA-DR+ ≥19%) or increased inflammation (high sensitivity C-reactive protein ≥2 mg/L). RESULTS:Overall, 77% were males and 70% African American. Mean (standard deviation) age and body mass index were 47 (10) years and 28 (6.4) kg/m(2), respectively. All subjects had HIV-1 RNA <1000 copies/mL with mean (standard deviation) CD4+ T cell count of 665 (280) cells/μL; 50% were on a protease inhibitor. EAT and TAT were correlated with each other (r = 0.766, p < 0.0001). Both were associated with metabolic syndrome, atherogenic lipid profile, insulin resistance, total and central body fat, serum biomarkers of inflammation, and soluble CD163, but not with cellular immune activation markers. In multivariable models that adjusted for age, sex, and other measures of adiposity, both perivascular fat depots were independently associated with the presence of coronary calcium. CONCLUSIONS:Perivascular fat is associated with soluble CD163, biomarkers of inflammation, insulin resistance, and subclinical atherosclerosis in this population of virologically suppressed HIV-infected patients on ART. The association of perivascular fat with coronary artery calcification appears to be independent of other measures of adiposity.

背景与目标： 背景：HIV感染的特点是尽管有效的抗逆转录病毒疗法（ART）仍持续存在慢性免疫激活，并且与心血管疾病的风险增加有关。特定的血管周围脂肪库是否与HIV的炎症相关尚不清楚。
方法：在一项横断面研究中，通过计算机X线断层摄影术以稳定的抗逆转录病毒疗法（胆固醇）≤130mg / dL的100名受HIV感染的成年人，通过计算机体层摄影术测量了心外膜（EAT）和胸主动脉周围（TAT）的脂肪组织体积T细胞活化增强（CD8 CD38 HLA-DR≥19％）或炎症增加（高敏C反应蛋白≥2 mg / L）。
结果：总体而言，男性占77％，非裔美国人占70％。平均年龄（标准差）和体重指数分别为47（10）岁和28（6.4）kg / m（2）。所有受试者的HIV-1 RNA <1000拷贝/ mL，平均（标准差）CD4 T细胞计数为665（280）细胞/μL； 50％使用蛋白酶抑制剂。 EAT和TAT相互关联（r = 0.766，p <0.0001）。两者均与代谢综合征，动脉粥样硬化脂质分布，胰岛素抵抗，总和中体脂肪，炎症的血清生物标志物和可溶性CD163有关，但与细胞免疫激活标志物无关。在针对年龄，性别和其他肥胖测量方法进行调整的多变量模型中，两个血管周围脂肪库都与冠状动脉钙离子的存在独立相关。
结论：在ART上，该人群在病毒学抑制的HIV感染患者中与可溶性CD163，炎症，胰岛素抵抗和亚临床动脉粥样硬化的生物标志物有关。血管周围脂肪与冠状动脉钙化的相关性似乎与肥胖的其他指标无关。

BACKGROUND & AIMS: :DNA damage could lead to the accumulation of cytosolic DNA, and the cytosolic DNA-sensing pathway has been implicated in multiple inflammatory diseases. However, the role of cytosolic DNA-sensing pathway in asthma pathogenesis is still unclear. This article explored the role of airway epithelial cyclic GMP-AMP synthase (cGAS), the major sensor of cytosolic dsDNA, in asthma pathogenesis. Cytosolic dsDNA accumulation in airway epithelial cells (ECs) was detected in the setting of allergic inflammation both in vitro and in vivo. Mice with cGAS deletion in airway ECs were used for OVA- or house dust mite (HDM)-induced allergic airway inflammation. Additionally, the effects of cGAS knockdown on IL-33-induced GM-CSF production and the mechanisms by which IL-33 induced cytosolic dsDNA accumulation in human bronchial epithelial (HBE) cells were explored. Increased accumulation of cytosolic dsDNA was observed in airway epithelium of OVA- or HDM-challenged mice and in HBE cells treated with IL-33. Deletion of cGAS in the airway ECs of mice significantly attenuated the allergic airway inflammation induced by OVA or HDM. Mechanistically, cGAS participates in promoting TH2 immunity likely via regulating the production of airway epithelial GM-CSF. Furthermore, Mito-TEMPO could reduce IL-33-induced cytoplasmic dsDNA accumulation in HBE cells possibly through suppressing the release of mitochondrial DNA into the cytosol. In conclusion, airway epithelial cGAS plays an important role via sensing the cytosolic dsDNA in asthma pathogenesis and could serve as a promising therapeutic target against allergic airway inflammation.

背景与目标： DNA损伤可能导致胞质DNA的积累，并且胞质DNA的传感途径与多种炎症性疾病有关。但是，尚不清楚胞质DNA传感途径在哮喘发病中的作用。本文探讨了气道上皮环状GMP-AMP合酶（cGAS）（胞质dsDNA的主要传感器）在哮喘发病中的作用。在体外和体内过敏性炎症的情况下，都检测到气道上皮细胞（ECs）中的胞质dsDNA积累。气道EC中具有cGAS缺失的小鼠用于OVA或屋尘螨（HDM）诱发的过敏性气道炎症。另外，探索了cGAS敲低对IL-33诱导的GM-CSF产生的影响，以及IL-33诱导人支气管上皮（HBE）细胞中胞质dsDNA积累的机制。在OVA或HDM攻击的小鼠的气道上皮以及用IL-33处理的HBE细胞中，观察到胞质dsDNA的积累增加。小鼠气道EC中cGAS的删除显着减轻了由OVA或HDM引起的过敏性气道炎症。从机制上讲，cGAS可能通过调节气道上皮GM-CSF的产生参与促进TH2免疫。此外，Mito-TEMPO可能通过抑制线粒体DNA释放到细胞质中来减少HBE细胞中IL-33诱导的胞质dsDNA积累。综上所述，气道上皮cGAS通过检测胞质中的dsDNA在哮喘发病中起着重要的作用，并且可以作为对抗变应性气道炎症的有希望的治疗靶标。