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：

BACKGROUND & AIMS: PURPOSE:The present study was aimed to evaluate the retinoprotective effects of Moringa oleifera (MO) in Streptozotocin-induced diabetic rats. METHODS:The study was continued for 24 weeks and evaluated for inflammatory (tumor necrosis factor [TNF]-α and interleukin [IL]-1β, angiogenic (vascular endothelial growth factor [VEGF] and protein kinase C [PKC]-β) and antioxidant (Glutathione, Superoxide dismutase, and Catalase) parameters. Retinal leakage was checked by Fluorescein angiography (FA) and fundus photographs were evaluated for retinal vessel caliber (arteriolar and venular). Transmission electron microscopy was done to determine basement membrane (BM) thickness. RESULTS:The results of the present study showed potential hypoglycemic and retinal antioxidant effects of MO. In the present study, a significant rise in the expression of retinal inflammatory (TNF-α and IL-1β) and angiogenic (VEGF and PKC-β) parameters was observed in diabetic retinae as compared to normal retinae. However, MO-treated retinae showed marked inhibition in the expression of inflammatory and angiogenic parameters. Further, in the present study, diabetic retinae showed dilated retinal vessels as compared to normal. However, MO-treated retinae showed marked prevention in the dilatation of retinal vessels. Fluorescein angiograms obtained from diabetic retinae showed leaky and diffused retinal vasculature. On the other hand, MO-treated retinae showed intact retinal vasculature. Further, results of the transmission electron microscopy study showed thickened capillary BM in the diabetic retina as compared to normal retinae. However, treatment with MO prevented thickening of capillary BM. CONCLUSION:Our result suggests that MO may be useful in preventing diabetes induced retinal dysfunction.

背景与目标：

BACKGROUND & AIMS: BACKGROUND AND OBJECTIVES:Olaratumab is a recombinant human monoclonal antibody that binds to platelet-derived growth factor receptor-α (PDGFRα). In a randomized phase II study, olaratumab plus doxorubicin met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement in overall survival versus doxorubicin alone in patients with advanced or metastatic soft tissue sarcoma (STS). In this study, we characterize the pharmacokinetics (PKs) of olaratumab in a cancer patient population. METHODS:Olaratumab was tested at 15 or 20 mg/kg in four phase II studies (in patients with nonsmall cell lung cancer, glioblastoma multiforme, STS, and gastrointestinal stromal tumors) as a single agent or in combination with chemotherapy. PK sampling was performed to measure olaratumab serum levels. PK data were analyzed by nonlinear mixed-effect modeling techniques using NONMEM®. RESULTS:The PKs of olaratumab were best described by a two-compartment PK model with linear clearance (CL). Patient body weight was found to have a significant effect on both CL and central volume of distribution (V 1), whereas tumor size significantly affected CL. A small subset of patients developed treatment-emergent anti-drug antibodies (TE-ADAs); however, TE-ADAs did not have any effect on CL or PK time course of olaratumab. There was no difference in the PKs of olaratumab between patients who received olaratumab as a single agent or in combination with chemotherapy. CONCLUSION:The PKs of olaratumab were best described by a model with linear disposition. Patient body weight and tumor size were found to be significant covariates. The PKs of olaratumab were not affected by immunogenicity or chemotherapeutic agents.

背景与目标：

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： : 当以预防性方式或在脓毒症或内毒素血症开始后早期给药时，褪黑素可改善生存和功能障碍，包括溶血，血小板减少症和低血压。在本研究中，褪黑激素不是在全身炎症的最初症状出现之前就给予的。以0.5 mg/kg × h的速率输注脂多糖以诱导雄性Wistar大鼠全身炎症。在开始脂多糖输注后180和270分钟静脉内施用褪黑素 (单剂量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，溶血和氨基转移酶活性; 血栓弹性测定参数; 和血小板计数) 定期确定。输注脂多糖会导致严重全身性炎症的特征性症状，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。尽管褪黑激素在全身性炎症的早期阶段可能具有有益的作用，但在重症监护病房中，褪黑激素很难成为明显败血症或内毒素血症的治疗选择。

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，在创伤或严重的细胞应激后释放或分泌。细胞外HMGB1触发炎症并将白细胞募集到组织损伤部位。我们回顾了最近的证据，即HMGB1募集白细胞的能力可能完全是由于与稳态趋化因子cxcl12形成了异复合物。HMGB1-CXCL12的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，只有HMGB1的一种氧化还原形式 (所有半胱氨酸被还原的一种) 可以结合cxcl12。含有C23和C45之间的二硫键的HMGB1和通过激活TLR4诱导趋化因子和细胞因子释放的HMGB1，以及末端氧化为含有半胱氨酸磺酸盐的HMGB1在募集白细胞中均无活性。因此，HMGB1的趋化因子和细胞因子诱导活性是可分离的，我们建议它们在炎症的发展及其消退过程中依次出现。HMGB1-CXCL12的异源复合物构成特定的靶标，可以有望治疗几种病理。

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：

BACKGROUND & AIMS: :M-type phospholipase A2 receptor (PLA2R) is the major target antigen in primary membranous nephropathy (PMN). Previous studies have evaluated the diagnostic value of serum anti-PLA2R antibody. However, the correlation of serum anti-PLA2R antibody and glomerular PLA2R deposition, and their association with clinical characteristics need to be further evaluated.A total of 136 patients were involved as inception group because serum anti-PLA2R antibody and glomerular PLA2R antigen were simultaneously measured. We examined serum anti-PLA2R antibody by ELISA and glomerular PLA2R deposition by immunofluorescence assay.Positive serum anti-PLA2R antibody and glomerular PLA2R deposition were seen in 58.8% (80/136) and 95.6% (130/136) patients, respectively (P < .001). Proteinuria, serum total protein, serum albumin, serum creatinine, and estimated glomerular filtration rate (eGFR) had significant differences between patients with serum anti-PLA2R antibody and those without. Serum anti-PLA2R antibody levels were correlated with serum albumin, serum creatinine, eGFR, and proteinuria. Glomerular PLA2R deposition intensities were weakly correlated with proteinuria. Unexpectedly, there was a positive correlation rather than a negative correlation between glomerular PLA2R deposition intensity and eGFR.In conclusion, serum anti-PLA2R antibody is more closely correlated with disease activity and renal function than glomerular PLA2R deposition.

背景与目标： : M型磷脂酶A2受体 (PLA2R) 是原发性膜性肾病 (PMN) 的主要靶抗原。先前的研究已经评估了血清anti-PLA2R抗体的诊断价值。但是，血清anti-PLA2R抗体与肾小球PLA2R沉积的相关性及其与临床特征的相关性有待进一步评估。共有136例患者作为起始组，因为同时测量了血清anti-PLA2R抗体和肾小球PLA2R抗原。ELISA法检测血清anti-PLA2R抗体，免疫荧光法检测肾小球PLA2R沉积，58.8% 例 (80/136例) 和95.6% 例 (130/136例) 血清anti-PLA2R抗体和肾小球PLA2R沉积阳性 (p  < .001)。蛋白尿，血清总蛋白，血清白蛋白，血清肌酐和估计的肾小球滤过率 (eGFR) 在具有血清anti-PLA2R抗体的患者与没有血清白蛋白的患者之间具有显着差异。血清anti-PLA2R抗体水平与血清白蛋白，血清肌酐，eGFR和蛋白尿相关。肾小球PLA2R沉积强度与蛋白尿的相关性较弱。不料，肾小球PLA2R沉积强度与eGFR呈正相关而非负相关，结论血清anti-PLA2R抗体与疾病活动和肾功能的相关性比肾小球PLA2R沉积更密切。

BACKGROUND & AIMS: :Novel treatment strategies for tuberculosis are urgently needed. Many different preclinical models assessing anti-tuberculosis drug activity are available, but it is yet unclear which combination of models is most predictive of clinical treatment efficacy. The aim of this study was to determine the role of our in vitro time kill-kinetics assay as an asset to a predictive preclinical modeling framework assessing anti-tuberculosis drug activity. The concentration- and time-dependent mycobacterial killing capacities of six anti-tuberculosis drugs were determined during exposure as single drugs or in dual, triple and quadruple combinations towards a Mycobacterium tuberculosis Beijing genotype strain and drug resistance was assessed. Streptomycin, rifampicin and isoniazid were most active against fast-growing M. tuberculosis. Isoniazid with rifampicin or high dose ethambutol were the only synergistic drug combinations. The addition of rifampicin or streptomycin to isoniazid prevented isoniazid resistance. In vitro ranking showed agreement with early bactericidal activity in tuberculosis patients for some but not all anti-tuberculosis drugs. The time-kill kinetics assay provides important information on the mycobacterial killing dynamics of anti-tuberculosis drugs during the early phase of drug exposure. As such, this assay is a valuable component of the preclinical modeling framework.

背景与目标： 迫切需要新的结核病治疗策略。有许多不同的评估抗结核药物活性的临床前模型，但尚不清楚哪种模型组合最能预测临床治疗效果。这项研究的目的是确定我们的体外时间杀伤动力学测定法作为评估抗结核药物活性的预测性临床前建模框架的资产的作用。在暴露于结核分枝杆菌北京基因型菌株的过程中，确定了六种抗结核药物的浓度和时间依赖性的分枝杆菌杀伤能力，并评估了耐药性。链霉素，利福平和异烟肼对快速生长的结核分枝杆菌最有效。异烟肼与利福平或高剂量乙胺丁醇是唯一的协同药物组合。在异烟肼中添加利福平或链霉素可防止异烟肼耐药性。体外排名显示，对于某些 (但不是所有) 抗结核药物，结核病患者的早期杀菌活性一致。时间杀伤动力学测定法提供了有关药物暴露早期抗结核药物的分枝杆菌杀伤动力学的重要信息。因此，该测定是临床前建模框架的有价值的组成部分。

BACKGROUND & AIMS: :Menyanthes trifoliata L. is used in Swedish traditional medicine for the treatment of inflammatory diseases of the kidney, e.g. glomerulonephritis. Earlier studies have shown that MtL increases glomerular filtration rate after renal reperfusion ischemia. This activity was suggested to be PAF-inhibitory since MtL also inhibited PAF-induced exocytosis in vitro on human neutrophils (IC(50) = 0.16 mg/ml). The present study further characterizes the anti-inflammatory properties of a rhizome decoction of this plant. MtL inhibited carrageenan-induced rat paw edema (ID(50) ≈ 1.7 g/kg p.o.) and ethyl phenylpropiolate-induced rat ear edema (32% at 2.0 g/kg p.o.) in a dose-dependent manner. Further studies revealed that MtL inhibited both fMLP-induced exocytosis (IC(50) = 0.16 mg/ml) and elastase activity (IC(50) = 0.16 mg/ml). According to these results it is likely that the activity shown in the PAF-test is at least partly due to an inhibition of elastase. MtL showed only minor hemolytic properties at the concentrations used in the PAF- and fMLP-tests, suggesting that the cells in these tests are undamaged. The decoction also inhibited the biosynthesis of LTB(4) (IC(50) ≈ 0.73 mg/ml) and prostaglandins (IC(50) = 0.37 mg/ml) in vitro in a concentration-dependent way. However, at concentrations where the decoction is active in the LTB(4)-test, it also possesses hemolytic properties.

背景与目标： : Menyanthes trifoliata L.在瑞典传统医学中用于治疗肾脏的炎症性疾病，例如肾小球肾炎。较早的研究表明，MtL会增加肾脏再灌注缺血后的肾小球滤过率。该活性被认为是PAF抑制的，因为MtL还抑制了PAF诱导的人嗜中性粒细胞的胞吐作用 (IC(50) = 0.16 mg/ml)。本研究进一步表征了该植物根茎汤的抗炎特性。MtL以剂量依赖性方式抑制角叉菜胶诱导的大鼠爪子水肿 (ID(50) ≈ 1.7g/kg p.o.) 和苯基丙醇酸乙酯诱导的大鼠耳水肿 (32% 2.0g/kg p.o.)。进一步的研究表明，MtL抑制fMLP诱导的胞吐作用 (IC(50) = 0.16 mg/ml) 和弹性蛋白酶活性 (IC(50) = 0.16 mg/ml)。根据这些结果，PAF测试中显示的活性可能至少部分归因于弹性蛋白酶的抑制。在PAF和fMLP测试中使用的浓度下，MtL仅显示出较小的溶血特性，这表明这些测试中的细胞未受损。该汤剂还以浓度依赖性方式抑制体外LTB(4) (IC(50) ≈ 0.73 mg/ml) 和前列腺素 (IC(50) = 0.37 mg/ml) 的生物合成。然而，在汤在LTB(4)-测试中具有活性的浓度下，它也具有溶血特性。

BACKGROUND & AIMS: :Anti-inflammatory and peroxisome proliferator-activated receptors (PPARs) transactivational effects of nine compounds (1 - 9) from the roots of Sophora flavescens were evaluated using NF-κB-luciferase, reverse transcriptase polymerase chain reaction, peroxisome proliferator response element (PPRE)-luciferase, and GAL-4-PPAR chimera assays. Compounds 4 and 8 significantly inhibited TNFα-induced NF-κB transcriptional activity in HepG2 cells in a dose-dependent manner, with IC₅₀ values of 4.0 and 4.4 μM, respectively. Furthermore, the transcriptional inhibitory function of these compounds was confirmed by a decrease in cyclooxgenase 2 and inducible nitric oxide synthase gene expression levels in HepG2 cells. Compounds 1, 3, 5, 6, 8, and 9 significantly activated the transcription of PPARs in a dose-dependent manner, with EC₅₀ values ranging from 1.1 to 13.0 μM. Compounds 1, 3, 5, 6, 8, and 9 exhibited dose-dependent PPARα transactivational activity, with EC₅₀ values in a range of 0.9 - 16.0 μM. Compounds 1, 3, 8, and 9 also significantly upregulated PPARγ activity in a dose-dependent manner, with EC₅₀ values of 10.5, 6.6, 15.7, and 1.6 μM, whereas compounds 1, 8, and 9 demonstrated transactivational PPARβ(δ) effects with EC₅₀ values of 11.4, 10.3, and 1.5 μM, respectively. These results provide a scientific rationale for the use of the roots of S. flavescens and warrant further studies to develop new agents for the prevention and treatment of inflammatory and metabolic diseases.

背景与目标： : 使用NF-κ b-荧光素酶，逆转录酶聚合酶链反应，过氧化物酶体增殖物反应元件 (PPRE)-荧光素酶评估了苦参根中的9种化合物 (1  -  9) 的抗炎和过氧化物酶增殖物激活受体 (ppar) 反式激活作用。GAL-4-PPAR嵌合体分析。化合物4和8以剂量依赖的方式显着抑制了tnf α 诱导的HepG2细胞中的NF-κ b转录活性，其ic of值分别为4.0和4.4  μ m。此外，这些化合物的转录抑制功能被HepG2细胞中环氧合酶2和诱导型一氧化氮合酶基因表达水平的降低所证实。化合物1、3、5、6、8和9以剂量依赖性方式显着激活ppar的转录，其值范围为1.1至13.0  μ m。化合物1、3、5、6、8和9表现出剂量依赖性ppar α 反式激活活性，其值在0.9  -  16.0  μ m的范围内。化合物1、3、8和9也以剂量依赖的方式显着上调ppar γ 活性，其e of value为10.5、6.6、15.7和1.6  μ m，而化合物1、8和9表现出反式激活ppar β(δ) 效应，其e of value为11.4、10.3，和1.5  μ m，分别。这些结果为使用S. flavescens的根提供了科学依据，并需要进一步研究以开发用于预防和治疗炎症和代谢疾病的新药物。

BACKGROUND & AIMS: :Selected plants documented as medicinal in an ethnobotanical study with the Nahua of the Sierra de Zongolica (Veracruz, Mexico) were evaluated for anti-inflammatory and antibacterial activity. One of the potential sides of action of anti-inflammatory drugs is the transcription factor NF-κB. This factor is essential for the immune, inflammatory, and acute phase responses. We therefore tested extracts from a total of 28 plants used by the Nahua Indians for their potential effect on the activation of the transcription factor NF-κB. The leaves of Tithonia diversifolia (Hemsl.) A. Gray (Asteraceae) was the only extract which showed inhibitory activity. Nonspecific DNA binding activities were not noticably influenced. Phytochemical studies to isolate the active principle and further biochemical studies in order to better understand the mode of action of this NF-κB inhibitor have been initiated. Five plants showed noteworthy antibacterial activity against some pathogenic (Staphylococcus aureus ATCC 25933 and Yersinia enterocolitica 03) and nonpathogenic (E. coli DSM 1077, Micrococcus luteus DSM 348) microorganism: Acacia cornigera, Cuscuta tinctoria, Ludwigia octovalvis, Lysiloma divaricata, and Tithonia diversifolia.

背景与目标： : 在一项民族植物学研究中与Sierra de Zongolica (墨西哥韦拉克鲁斯) 的Nahua进行了记录为药用植物的抗炎和抗菌活性评估。抗炎药物的潜在作用方面之一是转录因子NF-κ b。该因素对于免疫，炎症和急性期反应至关重要。因此，我们测试了纳华印第安人使用的总共28种植物的提取物对转录因子NF-κ b激活的潜在影响。Tithonia diversifolia (Hemsl.) A.Gray (菊科) 是唯一具有抑制活性的提取物。非特异性DNA结合活性没有受到明显影响。分离活性原理的植物化学研究和进一步的生化研究已经开始，以便更好地了解这种NF-κ b抑制剂的作用方式。五种植物对某些致病性 (金黄色葡萄球菌ATCC 25933和小肠结肠炎耶尔森氏菌03) 和非致病性 (大肠杆菌DSM 1077，微球菌DSM 348) 微生物具有显着的抗菌活性: 金相相思，刺槐，octovalvis，Lysiloma divaricata和Tithonia diversifolia。

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： : 胆汁酸在肝脏中合成，是胆汁中的主要成分。胆汁流动受损导致胆汁淤积，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。尽管胆汁淤积的原因已得到广泛研究，但有关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。这些包括胆汁淤积和胆汁淤积动物模型患者的肝细胞中的胆汁酸信号通路以及肝脏中胆管细胞和先天免疫细胞的反应。我们专注于胆汁酸如何触发中性粒细胞募集分子介质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，药物可能被认为是治疗胆汁淤积性肝损伤的有效疗法。

BACKGROUND & AIMS: :Since there are no systematic studies available on the effects of anti-microtubule agents on ciliated protozoa, we screened a wide variety of such compounds for their effects on the growth of Paramecium tetraurelia cell cultures. Compounds tested include agents of widely different chemical composition and with reported effects on widely different cell types. We can differentiate between different drug effects: (a) Rotenone is the only agent without any recognisable effect, (b) Another group of compounds (including colchicine) requires very high concentrations, as compared to higher animal cells, i.e., rather close to a cytotoxic level; this group also includes tubulozole (unexpectedly without any difference between the cis- and the trans-stereoisomer). (c) A third group of drugs inhibits cell culture growth without any lethal effects (benzimidazoles, nocodazole, parbendazole; the [anti-]fungal antibiotic, griseofulvin; the herbicide, trifluralin). (d) Finally a group of agents are active in a concentration range also reported for plants (the herbicide, APM) or for higher animal cells (including the microtubule stabiliser, taxol) or for both (vinblastine, vincristine, triethyl lead), although they are cytotoxic at higher concentrations (like compounds of group [b]). Therefore, in particular compounds of group (c) and possibly of group (d) might be considered further on for a more detailed analysis of a possibly genuine anti-microtubular effect in Paramecium cells. Of particular interest may be nocodazole, parbendazole and trifluralin, since they can inhibit cell culture growth (over 24 h tested) in relatively low concentrations (comparable to other cell types) without any impairment of cell viability.

背景与目标： : 由于尚无关于抗微管剂对纤毛原生动物的影响的系统研究，因此我们筛选了各种此类化合物对草履虫四重草细胞培养物生长的影响。测试的化合物包括化学成分广泛不同的试剂，据报道对细胞类型广泛不同的影响。我们可以区分不同的药物作用 :( a) 鱼藤酮是唯一没有任何可识别作用的药物，(b) 与较高的动物细胞相比，另一组化合物 (包括秋水仙碱) 需要非常高的浓度，即相当接近细胞毒性水平; 该组还包括小管 (出乎意料的是，顺式和反式立体异构体之间没有任何区别)。(c) 第三组药物抑制细胞培养物的生长，而没有任何致死作用 (苯并咪唑，诺考达唑，帕苯达唑; [抗] 真菌抗生素灰黄霉素; 除草剂，氟拉林)。(d) 最后，一组试剂在植物 (除草剂，APM) 或高等动物细胞 (包括微管稳定剂，紫杉醇) 或两者 (长春碱，长春新碱，三乙基铅) 的浓度范围内具有活性，尽管它们在较高浓度下具有细胞毒性 (如 [b] 组的化合物)。因此，特别是可以进一步考虑 (c) 组和 (d) 组的化合物，以更详细地分析草履虫细胞中可能真正的抗微管作用。特别令人感兴趣的可能是诺考达唑，帕苯达唑和三氟拉林，因为它们可以在相对较低的浓度 (与其他细胞类型相当) 下抑制细胞培养物生长 (测试超过24小时)，而不会损害细胞活力。

BACKGROUND & AIMS: :In this study, we investigated the anti-inflammatory effects and mechanisms of Hizikia fusiformis (HF) extracts in lipopolysaccharide (LPS)-induced RAW 264.7 cells. We extracted HF using solvent and sub-critical water techniques. In results, HF extracts inhibited nitric oxide (NO) production in cell-free and LPS-stimulated RAW 264.7 cells. HF210 (extract prepared with sub critical water at 210oC) was most effective. The HF210 extract dose-dependently inhibited inducible nitric oxide synthase expression (iNOS) and nuclear factor kappa (NF-B) p65 translocation from cytosol to the nucleus. Furthermore, HF210 extract dose-dependently inhibited the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), Jun N-terminal kinase (JNK), and signal transducers and activators of transcription (STAT)-1in LPS-induced RAW 264.7 cells. Thus, our results suggest that anti-inflammatory effects of HF210 extract showed a noticeable distinction by regulation of multiple signaling pathways in LPS-induced RAW 264.7 cells.

背景与目标： : 在这项研究中，我们研究了梭状冬青 (HF) 提取物在脂多糖 (LPS) 诱导的原始264.7细胞中的抗炎作用和机制。我们使用溶剂和亚临界水技术提取HF。结果，HF提取物抑制无细胞和LPS刺激的原始264.7细胞中一氧化氮 (NO) 的产生。HF210 (在210oC下用亚临界水制备的提取物) 最有效。HF210提取物剂量依赖性地抑制诱导型一氧化氮合酶 (iNOS) 表达和核因子 κ (NF-B) p65从细胞质到细胞核的转运。此外，HF210提取物在LPS诱导的原始264.7细胞中剂量依赖性地抑制p38丝裂原活化蛋白激酶 (p38mapk) 、6月N端激酶 (JNK) 和信号转导子和转录激活子 (STAT)-1的磷酸化。因此，我们的结果表明，HF210提取物的抗炎作用通过调节LPS诱导的原始264.7细胞中的多种信号通路显示出明显的区别。

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，并负责炎症部位常见的疼痛和肿胀。非甾体抗炎药 (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。然而，NSAID治疗的主要副作用之一是胃溃疡。通过5-脂氧合酶 (5-LO) 酶途径抑制前列腺素的产生和白三烯形成的相关增加可能导致吸引炎症细胞，引起局部炎症部位并产生溃疡。为了确定5-LO抑制对该假设的影响，在大鼠中进行了研究，以评估tepoxalin (一种双重CO/LO抑制剂) 对胃粘膜中白三烯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吲哚美辛 (在4天内每天2 mg/kg) 导致40% 死亡率，并在第四剂药物后24小时评估时伴有肠粘连和穿孔。此外，肠系膜小静脉中的中性粒细胞粘附增加，肠系膜间质中的细胞浸润明显。在每天吲哚美辛治疗前30分钟，在单独的大鼠组中抑制了这些胃肠道副作用。进行了进一步的研究以确定tepoxalin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，脂质过氧化物生成和LTB4生成。给药90分钟后，吲哚美辛 (100 mg/kg，p.o.) 在大鼠胃粘膜中产生升高的LTB4水平。此外，在该剂量下以及使用另一种NSAID萘普生时，肠系膜小静脉中的中性粒细胞粘附增加。此时，胃粘膜中没有明显的脂质过氧化物生成。Tepoxalin (最高400 mg/kg，p.o.) 对胃粘膜LTB4的生成和脂质过氧化物水平没有影响。在最高剂量下观察到中性粒细胞粘附减少。在另一项研究中，用tepoxalin (ED50 = 7.5 mg/kg，p.o.) 或选择性5-LO抑制剂zileuton (100 mg/kg，p.o.) 进行预处理可防止胃粘膜LTB4水平升高和中性粒细胞粘附由吲哚美辛 (100 mg/kg，p、o.)。这些数据表明，LO抑制作用可能在预防NSAID诱导的胃部炎症中起着至关重要的作用，从而深入了解tepoxalin缺乏溃疡性以及可能预防胃副作用的抗炎治疗的新方法。