BACKGROUND & AIMS: Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular levels of heme and hemeproteins; certain of the latter, i.e. cytochrome P450s, generate pro-inflammatory products from endogenous substrates. Two HO isozymes, the products of distinct genes, have been described; HO-1 is the inducible one, whereas HO-2 is believed to be constitutively expressed. We studied the inducing effects of several metal compounds [CoCl2, SnCl2, ZnCl2, heme, and cobalt protoporphyrin (CoPP)] on HO-1 mRNA content and enzyme activity in cultures of rabbit corneal epithelial (RCE) cells; these metal compounds are known to induce HO in other tissues. Additionally, we studied HO-1 expression in an experimental model of ocular inflammation produced in rabbit corneas by extended contact lens wear, and the relation of HO expression to the induced inflammatory process. SnCl2 added to RCE cells in vitro produced marked time- and concentration-dependent increases in HO-1 mRNA and HO-1 enzyme activity; CoCl2, ZnCl2, and CoPP were inducers of HO as well, though to a lesser degree than SnCl2. Corneas treated for 6 days with contact lenses impregnated with SnCl2 displayed substantially less corneal inflammation, swelling, and new vessel invasion than did controls; attenuation of ocular inflammation was paralleled by SnCl2-induced increases in HO mRNA and HO activity in corneal epithelial cells from treated eyes. It is suggested that amelioration of the inflammatory response produced by extended contact lens wear is due, in part, to the induction of high levels of HO-1 activity by SnCl2, which results in diminished production of pro-inflammatory mediators generated through heme-dependent metabolic processes. Regulation of HO activity in this manner may have clinical applications.

背景与目标： 血红素加氧酶（HO）通过将血红素分解为胆汁色素，从而下调血红素和血红蛋白的细胞水平。后者中的某些，即细胞色素P450，从内源性底物产生促炎性产物。已经描述了两种HO同功酶，它们是不同基因的产物。 HO-1是可诱导的，而HO-2被认为是组成型表达的。我们研究了几种金属化合物[CoCl2，SnCl2，ZnCl2，血红素和钴原卟啉（CoPP）]对兔角膜上皮（RCE）细胞培养物中HO-1 mRNA含量和酶活性的诱导作用。已知这些金属化合物会在其他组织中诱导HO。此外，我们研究了在长期角膜接触镜下兔子角膜产生的眼部炎症实验模型中HO-1的表达，以及HO表达与诱导的炎症过程的关系。体外添加到RCE细胞中的SnCl2在HO-1 mRNA和HO-1酶的活性上产生了明显的时间依赖性和浓度依赖性。 CoCl2，ZnCl2和CoPP也是HO的诱导剂，尽管程度要比SnCl2小。与对照组相比，用浸渍有SnCl2的隐形眼镜处理6天的角膜显示出的角膜发炎，肿胀和新血管侵袭明显少于对照组。眼炎症的减弱与SnCl2诱导处理过的眼睛的角膜上皮细胞中HO mRNA和HO活性增加有关。有人提出，延长隐形眼镜的佩戴会改善炎症反应，部分原因是SnCl2诱导了高水平的HO-1活性，这导致血红素依赖性促炎介质的产生减少。代谢过程。以这种方式调节HO活性可能具有临床应用。

BACKGROUND & AIMS: BACKGROUND:This study explored the combined impact of depression and inflammation on memory functioning among Mexican-American adults and elders. METHODS:Data were analyzed from 381 participants of the Health and Aging Brain study among Latino Elders (HABLE). Fasting serum samples were collected and assayed in duplicate using electrochemiluminesce on the SECTOR Imager 2400A from Meso Scale Discovery. Positive DepE (depression endophenotype) was codified as any score >1 on a five-point scale based on the GDS-30. Inflammation was determined by TNFα levels and categorized by tertiles (1st, 2nd, 3rd). WMS-III LMI and LMII as well as CERAD were utilized as measures of memory. ANOVAs examined group differences between positive DepE and inflammation tertiles with neuropsychological scale scores as outcome variables. Logistic regressions were used to examine level of inflammation and DepE positive status on the risk for MCI. RESULTS:Positive DepE as well as higher inflammation were both independently found to be associated with lower memory scores. Among DepE positive, those who were high in inflammation (3rd tertile) were found to perform significantly worse on WMS-III LM I (F = 4.75, p = 0.003), WMS-III LM II (F = 8.18, p < 0.001), and CERAD List Learning (F = 17.37, p < 0.001) when compared to those low on inflammation (1st tertile). The combination of DepE positive and highest tertile of inflammation was associated with increased risk for MCI diagnosis (OR = 6.06; 95% CI = 3.9-11.2, p < 0.001). CONCLUSION:Presence of elevated inflammation and positive DepE scores increased risk for worse memory among Mexican-American older adults. Additionally, the combination of DepE and high inflammation was associated with increased risk for MCI diagnosis. This work suggests that depression and inflammation are independently associated with worse memory among Mexican-American adults and elders; however, the combination of both increases risk for poorer memory beyond either alone.

背景与目标： 背景：这项研究探讨了抑郁症和炎症对墨西哥裔美国成年人和老年人记忆功能的综合影响。
方法：对来自拉丁裔老年人（HABLE）的381名健康与衰老脑研究参与者的数据进行了分析。收集空腹血清样品，并在来自Meso Scale Discovery的SECTOR Imager 2400A上使用电化学试剂进行一式两份的分析。阳性DepE（抑郁内表型）被编码为基于GDS-30的五分制中任何得分> 1。炎症由TNFα水平确定，并按三分位数（第1，第2，第3）分类。 WMS-III LMI和LMII以及CERAD被用作存储量度。方差分析使用神经心理学量表评分作为结果变量，检查了DepE阳性和炎症三分位数之间的组差异。 Logistic回归用于检查炎症水平和DepE阳性状态对MCI风险的影响。
结果：阳性DepE和较高的炎症都独立地与较低的记忆力分数相关。在DepE阳性中，发炎程度较高（第三三分位数）的患者被发现在WMS-III LM I（F = 4.75，p = 0.003），WMS-III LM II（F = 8.18，p <0.001）上表现明显较差。 ，和CERAD列表学习（F = 17.37，p <0.001）相比，炎症反应低下者（第一三分位）。 DepE阳性和最高发炎度的组合与MCI诊断的风险增加相关（OR = 6.06； 95％CI = 3.9-11.2，p <0.001）。
结论：墨西哥裔美国老年人的炎症增加和DepE得分阳性的存在增加了记忆力减退的风险。另外，DepE和高发炎的组合与MCI诊断的风险增加有关。这项工作表明，墨西哥裔美国成年人和老年人的抑郁和发炎与记忆力减退是独立相关的。但是，两者的结合会增加较差的记忆风险，而这两者都不是其中一个。

BACKGROUND & AIMS: :Melatonin improves survival and functional impairment including hemolysis, thrombocytopenia, and hypotension when administered in a prophylactic manner or early after initiation of sepsis or endotoxemia. In the present study, melatonin was given not before first symptoms of systemic inflammation became manifest. Lipopolysaccharide was infused at a rate of 0.5 mg/kg × h to induce systemic inflammation in male Wistar rats. Melatonin (single dose 3 mg/kg × 15 min) was intravenously administered 180 and 270 min after starting of the lipopolysaccharide infusion. Systemic and vital parameters (e.g., systemic blood pressure and breathing rate) as well as blood and plasma parameters (acid-base parameters; electrolytes; parameters of tissue injury such as glucose concentration, lactate concentration, hemolysis, and aminotransferase activities; parameters of thromboelastometry; and platelet count) were determined in regular intervals. Infusion of lipopolysaccharide led to characteristic symptoms of severe systemic inflammation including hypotension, metabolic acidosis and hypoglycemia, electrolyte and hemostatic disturbances, thrombocytopenia, and hemolysis. Melatonin neither decreased mortality nor reduced lipopolysaccharide-dependent changes to vital, blood, and plasma parameters. Even though melatonin may have a beneficial effect in early stages of systemic inflammation, it can hardly be an option in therapy of manifest sepsis or endotoxemia in an intensive care unit.

背景与目标： 褪黑素以预防性方式或在脓毒症或内毒素血症开始后的早期给药，可改善生存和功能障碍，包括溶血，血小板减少和低血压。在本研究中，褪黑激素未在系统性炎症的最初症状显现之前就给予。以0.5 mg / kg×h的速度注入脂多糖以诱导雄性Wistar大鼠全身性炎症。开始注入脂多糖后180和270分钟静脉注射褪黑激素（单次剂量3 mg / kg×15分钟）。全身和生命参数（例如全身血压和呼吸频率）以及血液和血浆参数（酸碱参数；电解质；组织损伤参数，例如葡萄糖浓度，乳酸浓度，溶血和转氨酶活性；血栓弹力测定法参数；以及血小板计数）是定期确定的。输注脂多糖会导致严重的全身炎症的特征性症状，包括低血压，代谢性酸中毒和低血糖，电解质和止血障碍，血小板减少症和溶血。褪黑激素既不能降低死亡率，也不能降低脂多糖依赖性的生命，血液和血浆参数变化。即使褪黑激素在全身性炎症的早期阶段可能具有有益的作用，但在重症监护病房治疗明显的败血症或内毒素血症时，它几乎不是一种选择。

BACKGROUND & AIMS: :HMGB1 is a nuclear protein that is released or secreted following trauma or severe cellular stress. Extracellular HMGB1 triggers inflammation and recruits leukocytes to the site of tissue damage. We review recent evidence that the ability of HMGB1 to recruit leukocytes may be entirely due to the formation of a heterocomplex with the homeostatic chemokine CXCL12. The HMGB1-CXCL12 heterocomplex acts on the CXCR4 receptor more potently than CXCL12 alone. Notably, only one of the redox forms of HMGB1, the one where all cysteines are reduced (all-thiol), can bind CXCL12. Both HMGB1 containing a disulfide bond between C23 and C45, which induces chemokine and cytokine release by activating TLR4, and HMGB1 terminally oxidized to contain a cysteine sulfonate are inactive in recruiting leukocytes. Thus, the chemoattractant and cytokine-inducing activities of HMGB1 are separable, and we propose that they appear sequentially during the development of inflammation and its resolution. The HMGB1-CXCL12 heterocomplex constitutes a specific target that may hold promise for the treatment of several pathologies.

背景与目标： ：HMGB1是一种核蛋白，在外伤或严重的细胞应激后会释放或分泌。细胞外HMGB1引发炎症，并将白细胞募集到组织损伤部位。我们审查了最近的证据，HMGB1募集白细胞的能力可能完全是由于与稳态趋化因子CXCL12形成异源复合体。 HMGB1-CXCL12异源复合物比单独的CXCL12更有效地作用于CXCR4受体。值得注意的是，HMGB1的一种氧化还原形式（所有半胱氨酸都被还原的形式（全硫醇））可以结合CXCL12。 HMGB1在C23和C45之间包含二硫键，可通过激活TLR4诱导趋化因子和细胞因子释放，而HMGB1最终被氧化以包含半胱氨酸磺酸盐，在募集白细胞方面均无活性。因此，HMGB1的趋化性和细胞因子诱导活性是可分离的，我们建议它们在炎症发展和消退过程中依次出现。 HMGB1-CXCL12异源复合物构成了一个特定的靶标，有望为多种病理学的治疗带来希望。

BACKGROUND & AIMS: OBJECTIVES:Tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is caused by TNFRSF1A mutations, known to induce intracellular retention of the TNFα receptor 1 (TNFR1) protein, defective TNFα-induced apoptosis, and production of reactive oxygen species. As downregulation of autophagy, the main cellular pathway involved in insoluble aggregate elimination, has been observed to increase the inflammatory response, we investigated whether it plays a role in TRAPS pathogenesis. METHODS:The possible link between TNFRSF1A mutations and inflammation in TRAPS was studied in HEK-293T cells, transfected with expression constructs for wild-type and mutant TNFR1 proteins, and in monocytes derived from patients with TRAPS, by investigating autophagy function, NF-κB activation and interleukin (IL)-1β secretion. RESULTS:We found that autophagy is responsible for clearance of wild-type TNFR1, but when TNFR1 is mutated, the autophagy process is defective, probably accounting for mutant TNFR1 accumulation as well as TRAPS-associated induction of NF-κB activity and excessive IL-1β secretion, leading to chronic inflammation. Autophagy inhibition due to TNFR1 mutant proteins can be reversed, as demonstrated by the effects of the antibiotic geldanamycin, which was found to rescue the membrane localisation of mutant TNFR1 proteins, reduce their accumulation and counteract the increased inflammation by decreasing IL-1β secretion. CONCLUSIONS:Autophagy appears to be an important mechanism in the pathogenesis of TRAPS, an observation that provides a rationale for the most effective therapy in this autoinflammatory disorder. Our findings also suggest that autophagy could be proposed as a novel therapeutic target for TRAPS and possibly other similar diseases.

背景与目标： 目的：肿瘤坏死因子（TNF）受体相关的周期性综合征（TRAPS）是由TNFRSF1A突变引起的，该突变已知可诱导TNFα受体1（TNFR1）蛋白的细胞内滞留，缺陷性TNFα诱导的细胞凋亡以及活性氧的产生。由于自噬的下调，参与不溶性聚集物消除的主要细胞途径，已被观察到会增加炎症反应，因此我们研究了它是否在TRAPS发病机理中起作用。
方法：通过研究自噬功能NF-κB，研究了HEK-293T细胞，野生型和突变TNFR1蛋白的表达构建体转染的TRAPS患者和源自TRAPS患者的单核细胞中TNFRSF1A突变与TRAPS炎症之间的可能联系。激活和白介素（IL）-1β分泌。
结果：我们发现自噬是野生型TNFR1清除的原因，但是当TNFR1突变时，自噬过程是有缺陷的，这可能是突变TNFR1积累以及TRAPS相关的NF-κB活性和过度IL-诱导的原因。 1β分泌，导致慢性炎症。可以逆转由TNFR1突变蛋白引起的自噬抑制作用，如抗生素格尔德霉素的作用所证明的那样，该结果被发现可以挽救突变TNFR1蛋白的膜定位，减少其积聚并通过减少IL-1β分泌来抵消炎症的增加。
结论：自噬似乎是TRAPS发病机制中的重要机制，这一观察结果为这种自发炎性疾病的最有效治疗提供了理论依据。我们的发现还表明自噬可以被提议作为TRAPS和其他可能的类似疾病的新型治疗靶标。

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。