• 【过氧化物酶体增殖物激活受体配体的直接抗氧化和抗炎作用与链脲佐菌素诱导的糖尿病大鼠主动脉中血管紧张素转化酶表达的抑制有关。】 复制标题 收藏 收藏
    DOI:10.1016/j.ejphar.2006.08.036 复制DOI
    作者列表:Toba H,Miki S,Shimizu T,Yoshimura A,Inoue R,Sawai N,Tsukamoto R,Murakami M,Morita Y,Nakayama Y,Kobara M,Nakata T
    BACKGROUND & AIMS: :Peroxisome proliferator-activated receptors (PPARs) are expressed on vascular tissue. To investigate the direct vasoprotective effects of PPARgamma and PPARalpha ligands, pioglitazone (3 mg/kg/day) and bezafibrate (10 mg/kg/day) were given by gavage to streptozotocin-induced diabetic rats for 4 weeks. Streptozotocin (65 mg/kg, i.p.) significantly increased NADPH oxidase, vascular call adhesion molecule-1 (VCAM-1), and osteopontin mRNA levels in the aorta, as determined by reverse transcription (RT)-polymerase chain reaction (PCR). Immunohistochemical analysis revealed that the expression of osteopontin protein was also enhanced in the streptozotocin-injected rat aorta. Pioglitazone or bezafibrate attenuated the streptozotocin-induced increase in the expression of NADPH oxidase and VCAM-1 mRNA. The enhanced expression of osteopontin gene and protein induced by streptozotocin was suppressed by pioglitazone, whereas treatment with bezafibrate had no effect on the expression of osteopontin. We also demonstrated that pioglitazone or bezafibrate prevented the streptozotocin-induced increase in angiotensin converting enzyme (ACE) gene and protein content, by the means of RT-PCR and Western blotting. On the other hand, the treatment of pioglitazone or bezafibrate in the present study did not affect glucose tolerance, serum insulin or lipid level in streptozotocin-induced diabetic rats. These results suggest that the direct anti-oxidant and anti-inflammatory effects of PPARs ligands in the aorta of streptozotocin-induced diabetic rats were not likely to have been mediated by the normalization of glucose or lipid metabolism, but instead these salutary effects appear to have been associated with the inhibition of the expression of ACE. In addition, pioglitazone appeared to be more effective on the suppression of osteopontin expression compared with bezafibrate.
    背景与目标: : 过氧化物酶体增殖物激活受体 (ppar) 在血管组织上表达。为研究PPARgamma和PPARalpha配体的直接血管保护作用,将吡格列酮 (3 mg/kg/天) 和苯扎贝特 (10 mg/kg/天) 灌胃给链脲佐菌素诱导的糖尿病大鼠4周。通过逆转录 (RT)-聚合酶链反应 (PCR) 测定,链脲佐菌素 (65 mg/kg,i.p.) 显着增加主动脉中的NADPH氧化酶,血管呼叫粘附分子-1 (VCAM-1) 和骨桥蛋白mRNA水平。免疫组织化学分析显示,在注射链脲佐菌素的大鼠主动脉中,骨桥蛋白的表达也得到了增强。吡格列酮或苯扎贝特减弱了链脲佐菌素诱导的NADPH氧化酶和VCAM-1 mRNA表达的增加。吡格列酮抑制了链脲佐菌素诱导的骨桥蛋白基因和蛋白的增强表达,而苯扎贝特治疗对骨桥蛋白的表达没有影响。我们还证明,吡格列酮或苯扎贝特通过rt-pcr和Western印迹阻止了链脲佐菌素诱导的血管紧张素转化酶 (ACE) 基因和蛋白质含量的增加。另一方面,本研究中吡格列酮或苯扎贝特的治疗不会影响链脲佐菌素诱导的糖尿病大鼠的葡萄糖耐量,血清胰岛素或脂质水平。这些结果表明,链脲佐菌素诱导的糖尿病大鼠主动脉中ppar配体的直接抗氧化和抗炎作用不太可能由葡萄糖或脂质代谢的正常化介导。但是,这些有益的作用似乎与抑制ACE的表达有关。此外,与苯扎贝特相比,吡格列酮似乎对抑制骨桥蛋白表达更有效。
  • 2 Sirtuins as emerging anti-parasitic targets. 复制标题 收藏 收藏

    【Sirtuins是新兴的抗寄生虫靶标。】 复制标题 收藏 收藏
    DOI:10.1016/j.ejmech.2012.11.014 复制DOI
    作者列表:Zheng W
    BACKGROUND & AIMS: :Silent information regulator 2 (Sir2) enzymes or sirtuins are a family of NAD(+)-dependent protein N(ε)-acetyl-lysine (AcK) deacetylases. Sirtuins are also evolutionarily conserved proteins that are present in all kingdoms of life ranging from bacteria to humans. Interestingly, it was recently found that the sirtuins found in various human parasites (especially the Plasmodium, Trypanosoma, and Leishmania species) were pro-survival for the parasites under various conditions. Therefore, these parasitic sirtuins have emerged as novel anti-parasitic therapeutic targets. This article reviews the currently available structural, biochemical, pharmacological, and medicinal chemistry studies on these enzymes, and discusses the perspectives of selectively targeting the parasitic sirtuins as a novel therapeutic strategy for the human parasitic diseases.
    背景与目标: : 沉默信息调节因子2 (Sir2) 酶或sirtuins是NAD () 依赖性蛋白N(ε)-乙酰赖氨酸 (AcK) 脱乙酰基酶的家族。Sirtuins也是进化上保守的蛋白质,存在于从细菌到人类的所有生命王国中。有趣的是,最近发现在各种人类寄生虫 (尤其是疟原虫,锥虫和利什曼原虫) 中发现的sirtuins在各种条件下都是寄生虫的生存。因此,这些寄生sirtuins已成为新的抗寄生虫治疗靶标。本文回顾了目前对这些酶的结构,生化,药理和药物化学研究,并讨论了选择性靶向寄生虫sirtuins作为人类寄生虫病新治疗策略的观点。
  • 【辣木通过抗氧化剂,抗炎和抗血管生成机制对链脲佐菌素诱导的糖尿病大鼠的视网膜保护作用。】 复制标题 收藏 收藏
    DOI:10.1089/jop.2012.0089 复制DOI
    作者列表:Kumar Gupta S,Kumar B,Srinivasan BP,Nag TC,Srivastava S,Saxena R,Aggarwal A
    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:
  • 【抗pdgfr α 人单克隆抗体Olaratumab在晚期和/或转移性癌症患者中的群体药代动力学模型。】 复制标题 收藏 收藏
    DOI:10.1007/s40262-017-0562-0 复制DOI
    作者列表:Mo G,Baldwin JR,Luffer-Atlas D,Ilaria RL Jr,Conti I,Heathman M,Cronier DM
    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:
  • 【中国膜性肾病患者血清anti-PLA2R抗体和肾小球PLA2R沉积: 一项横断面研究。】 复制标题 收藏 收藏
    DOI:10.1097/MD.0000000000007218 复制DOI
    作者列表:Pang L,Zhang AM,Li HX,Du JL,Jiao LL,Duan N,Liu Y,Yu D
    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。
  • 【维持负液体平衡可以改善原发性高血压患者的内皮和心脏功能。】 复制标题 收藏 收藏
    DOI:10.1080/10641963.2017.1291663 复制DOI
    作者列表:Yeşiltepe A,Dizdar OS,Gorkem H,Dondurmacı E,Ozkan E,Koç A,Oguz Baktır A,Gunal AI
    BACKGROUND & AIMS: PURPOSE:The issue of unidentified volume expansion is well recognized as a cause for resistance to antihypertensive therapy. The aim of study is to identify contribution of negative fluid balance to hypertension control and impact on endothelial and cardiac functions among primary hypertensive patients who do not have kidney failure. MATERIALS AND METHODS:This is a prospective interventional study with one-year follow-up. Preceded by volume status measurements were performed by a body composition monitor (BCM), the patients were put on ambulatory blood pressure monitoring for 24 hours. Then, echocardiographic assessments and flow-mediated dilation (FMD) and carotid intima-media thickness (CIMT) measurements were completed. Patients in one of the two groups were kept negative hydrated during trial with diuretic treatment. RESULTS:At the end of one-year follow-up, patients in negative hydrated group were found to have significantly lower CIMT, left ventricle mass index, left ventricular end-diastolic diameter, mean systolic and diastolic BP, non-dipper patient ratio, and higher FMD. In negatively hydrated group, target organ damage significantly reduced during trial. CONCLUSIONS:The significance of negative hydration status with respect to blood pressure control, endothelial and cardiac functions within primary hypertensive patients who do not suffer from kidney failure has been demonstrated.
    背景与目标:
  • 【作为评估抗结核药物活性的临床前建模框架的一部分,时间终止动力学测定法的作用。】 复制标题 收藏 收藏
    DOI:10.1016/j.tube.2017.04.010 复制DOI
    作者列表:Bax HI,Bakker-Woudenberg IAJM,de Vogel CP,van der Meijden A,Verbon A,de Steenwinkel JEM
    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。
  • 【对三叶Menyanthes的抗炎研究与对大鼠肾衰竭的作用有关。】 复制标题 收藏 收藏
    DOI:10.1016/S0944-7113(11)80054-1 复制DOI
    作者列表:Tunón H,Bohlin L
    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。
  • 【苦参根黄酮的抗炎和PPAR反激活特性。】 复制标题 收藏 收藏
    DOI:10.1002/ptr.4871 复制DOI
    作者列表:Quang TH,Ngan NT,Minh CV,Kiem PV,Tai BH,Nhiem NX,Thao NP,Luyen BT,Yang SY,Kim YH
    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。
  • 【纳华印度药用植物 (墨西哥): 作为抗炎模型对NF-κ b的抑制活性和抗菌作用。】 复制标题 收藏 收藏
    DOI:10.1016/S0944-7113(96)80064-X 复制DOI
    作者列表:Bork PM,Schmitz ML,Weimann C,Kist M,Heinrich M
    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。
  • 【抗微管剂对草履虫细胞培养生长的影响。】 复制标题 收藏 收藏
    DOI:10.1016/S0932-4739(11)80066-0 复制DOI
    作者列表:Pape R,Kissmehl R,Glas-Albrecht R,Plattner H
    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。
  • 【多细胞信号通路在脂多糖诱导的原始264.7细胞中的抗炎作用及其机制。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Sharma BR,Park CS,Ma SJ,Rhyu DY
    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。
  • 【染料木黄酮的慢性给药可改善自发性高血压大鼠的内皮功能障碍: eNOS,caveolin和钙调蛋白表达以及NADPH氧化酶活性的参与。】 复制标题 收藏 收藏
    DOI:10.1042/CS20060185 复制DOI
    作者列表:Vera R,Sánchez M,Galisteo M,Villar IC,Jimenez R,Zarzuelo A,Pérez-Vizcaíno F,Duarte J
    BACKGROUND & AIMS: :The soya-derived phytoestrogen genistein has been suggested to be protective in cardiovascular diseases. In the present study, we have analysed whether chronic oral genistein might influence endothelial function in male SHRs (spontaneously hypertensive rats) via ERs (oestrogen receptors), changes in eNOS (endothelial NO synthase) activity and vascular O(2)(-) (superoxide) production. Rats (23-weeks old) were divided into the following groups: WKY (Wistar-Kyoto)-vehicle, SHR-vehicle, WKY-genistein (10 mg.kg(-1) of body weight.day(-1)); SHR-genistein; SHR-genistein-faslodex (ICI 182780; 2.5 mg.kg(-1) of body weight.day(-1)). Vascular expression of eNOS, caveolin-1 and calmodulin-1 were analysed by Western blotting, eNOS activity by conversion of [(3)H]arginine into L-[(3)H]citrulline and O(2)(-) production by chemoluminescence of lucigenin. In SHRs, after 5 weeks of treatment, genistein reduced systolic blood pressure and enhanced endothelium-dependent aortic relaxation to acetylcholine, but had no effect on the vasodilator responses to sodium nitroprusside. Compared with WKY rats, SHRs had up-regulated eNOS and down-regulated caveolin-1 and calmodulin-1 expression, increased NADPH-induced O(2)(-) production, but reduced eNOS activity. Genistein increased aortic calmodulin-1 protein abundance and eNOS activity, and reduced NADPH-induced O(2)(-) production in SHRs. The pure ERalpha and ERbeta antagonist faslodex did not modify any of the changes induced by genistein in SHRs, suggesting that these effects are unrelated to ER stimulation. In conclusion, genistein reduced the elevated blood pressure and endothelial dysfunction in SHRs. This latter effect appears to be related to increased eNOS activity associated with increased calmodulin-1 expression and decreased O(2)(-) generation.
    背景与目标: : 大豆衍生的植物雌激素染料木黄酮被认为对心血管疾病具有保护作用。在本研究中,我们分析了慢性口服染料木黄酮是否可能通过ERs (雌激素受体),eNOS (内皮NO合酶) 活性的变化和血管O(2)(-) 影响雄性shr (自发性高血压大鼠) 的内皮功能 (超氧化物) 产生。将大鼠 (23周龄) 分为以下组: WKY (Wistar-Kyoto)-载体,SHR-载体,WKY-染料木黄酮 (10 mg.kg(-1) 体重)。天 (-1)); SHR-染料木黄酮; SHR-genistein-faslodex (ICI 182780; 体重2.5 mg.kg(-1) 天 (-1))。通过蛋白质印迹法分析eNOS,caveolin-1和calmodulin-1的血管表达,通过将 [(3)H] 精氨酸转化为L-[(3)H] 瓜氨酸和通过荧光素的化学发光产生O(2)(-) 的eNOS活性。在shr中,治疗5周后,金雀异黄素降低了收缩压,增强了内皮依赖性主动脉对乙酰胆碱的舒张作用,但对硝普钠的血管舒张反应没有影响。与WKY大鼠相比,SHRs上调了eNOS,下调了caveolin-1和calmodulin-1表达,增加了NADPH诱导的O(2)(-) 产生,但降低了eNOS活性。染料木黄酮增加了主动脉calmodulin-1蛋白丰度和eNOS活性,并降低了NADPH诱导的shr中O(2)(-) 的产生。纯的ERalpha和ERbeta拮抗剂faslodex没有改变由染料木黄酮在shr中诱导的任何变化,提示这些作用与ER刺激无关。总之,染料木黄酮降低了shr的血压升高和内皮功能障碍。后一种作用似乎与与calmodulin-1表达增加和O(2)(-) 生成减少相关的eNOS活性增加有关。
  • 【Anti-Ro52抗体经常与特发性炎症性肌病患者血清中的anti-Jo-1抗体同时出现。】 复制标题 收藏 收藏
    DOI:10.1046/j.1365-2249.1997.4081308.x 复制DOI
    作者列表:Rutjes SA,Vree Egberts WT,Jongen P,Van Den Hoogen F,Pruijn GJ,Van Venrooij WJ
    BACKGROUND & AIMS: We analysed 112 idiopathic inflammatory myopathy (IIM) sera for the presence of anti-Ro, anti-La and anti-histidyl-tRNA synthetase (Jo-1) autoantibodies, and subsequently mapped B cell epitopes on the Ro52 protein recognized by anti-Ro52+ IIM sera. Sera were characterized by immunoblotting, ELISA and RNA precipitation. Both anti-Ro60 and anti-La activity was found in 4% of IIM sera. Anti-Ro52 antibodies were present in 20% of IIM sera. However, in anti-Jo-1+ IIM sera (21%), the frequency of the anti-Ro52 antibodies was found to be much higher (58%). No cross-reactivity between anti-Ro52 and anti-Jo-1 antibodies could be detected in these sera. To learn more about the nature of anti-Ro52 antibodies occurring in IIM sera, we analysed the major epitopes of the Ro52 protein targeted by anti-Ro52+ IIM sera by immunoprecipitation of in vitro translated Ro52 deletion mutants. The major epitope was mapped in the region bordered by amino acids 126 and 252. This part of the protein includes a long alpha-helical region which contains two potential coiled-coil domains as well as a leucine zipper motif. Although no difference in Ro52 epitope recognition between anti-Jo-1+ and anti-Jo-1- IIM sera could be observed, our results suggest that the autoimmune response against Ro52 and Jo-1 in IIM patients is coupled.

    背景与目标: 我们分析了112个特发性炎症性肌病 (IIM) 血清中存在抗Ro,抗La和抗组氨酸-tRNA合成酶 (Jo-1) 自身抗体,随后将b细胞表位绘制在anti-Ro52 IIM血清识别的Ro52蛋白上。通过免疫印迹,ELISA和RNA沉淀对血清进行表征。在4% 的IIM血清中发现了anti-Ro60和抗La活性。Anti-Ro52抗体存在于IIM血清的20% 中。然而,在anti-Jo-1 + IIM血清 (21%) 中,发现anti-Ro52抗体的频率要高得多 (58%)。在这些血清中未检测到anti-Ro52和anti-Jo-1抗体之间的交叉反应。为了更多地了解IIM血清中anti-Ro52抗体的性质,我们通过体外翻译的Ro52缺失突变体的免疫沉淀分析了anti-Ro52 IIM血清靶向的Ro52蛋白的主要表位。主要表位被定位在与氨基酸126和252接壤的区域中。蛋白质的这一部分包括一个长的 α 螺旋区域,该区域包含两个潜在的卷曲螺旋结构域以及亮氨酸拉链基序。尽管在anti-Jo-1和anti-Jo-1- IIM血清之间没有观察到Ro52表位识别的差异,但我们的结果表明IIM患者针对Ro52和Jo-1的自身免疫反应是偶联的。
  • 【在高胰岛素血症,胰岛素抵抗和高血压大鼠中,用米贝拉地慢性T型Ca2通道阻断。】 复制标题 收藏 收藏
    DOI:10.1016/s0008-6363(97)00032-1 复制DOI
    作者列表:Verma S,Bhanot S,Hicke A,McNeill JH
    BACKGROUND & AIMS: OBJECTIVES:To determine the effects of calcium antagonists on hyperinsulinemia, hypertriglyceridemia and hypertension, we examined the long-term effects of a new calcium channel blocker, mibefradil, on plasma insulin levels, plasma triglyceride levels and systolic blood pressure in insulin-resistant and hyperinsulinemic fructose-hypertensive (FH) rats. To this aim, both prevention and reversal protocols were employed.

    METHODS:Prevention study: Male Sprague-Dawley rats were procured at 6 weeks of age and were divided into: control (C, n = 6), control-treated (CT, n = 5), fructose (F, n = 7) and fructose-treated (FT, n = 6). Baseline measurements of plasma glucose, insulin and systolic blood pressure were conducted in all groups. At week 7, chronic mibefradil treatment (30 mg/kg/day, orally for 6 weeks) was initiated in the CT and FT groups. At week 8, the rats in the F and FT groups were started on a 66% fructose diet to induce hyperinsulinemia and hypertension. Weekly measurements of plasma insulin, plasma triglycerides and systolic blood pressure were conducted for the following 4 weeks. Reversal protocol: In a separate study, 8-week-treated FH rats and their age-matched controls were used to examine the effects of mibefradil on reversing fructose-induced hyperinsulinemia and hypertension.

    RESULTS:The F group exhibited hyperinsulinemia (3.2 +/- 0.1 vs. C 2.3 +/- 0.07 ng/ml, P < 0.05), hypertension (148 +/- 3 vs. C 121 +/- 1 mmHg, P < 0.002) and elevated triglyceride levels (5.4 +/- 0.8 vs. C 1.6 +/- 0.3 mM, P < 0.05). Chronic mibefradil treatment prevented the development of hyperinsulinemia (1.6 +/- 0.08 ng/ml, P < 0.004 vs. F) and hypertension (123 +/- 1 mmHg. P < 0.001 vs. F) and attenuated the development of hypertriglyceridemia. In the reversal study, mibefradil treatment reversed the development of hyperinsulinemia, hypertriglyceridemia and elevated BP in FH rats. Treatment did not affect the plasma glucose levels in any group (prevention or reversal).

    CONCLUSIONS:Long-term treatment with the calcium antagonist, mibefradil, both prevents and reverses the development of hyperinsulinemia, hypertriglyceridemia and hypertension in FH rats. These data indicate beneficial effects of mibefradil on carbohydrate and lipid metabolism in hyperinsulinemic and insulin-resistant states.

    背景与目标: 目的 : 为了确定钙拮抗剂对高胰岛素血症,高甘油三酯血症和高血压的影响,我们检查了新型钙通道阻滞剂mibefradil对血浆胰岛素水平的长期影响,胰岛素抵抗和高胰岛素性果糖高血压 (FH) 大鼠的血浆甘油三酸酯水平和收缩压。为此,采用了预防和逆转方案。
    方法 : 预防研究: 雄性Sprague-Dawley大鼠在6周龄时被购买,并分为: 对照组 (C,n = 6),对照处理 (CT,n = 5),果糖 (F,n = 7) 和果糖处理 (FT,n = 6)。所有组均进行了血糖,胰岛素和收缩压的基线测量。在第7周时,CT和FT组开始了慢性mibefradil治疗 (30 mg/kg/天,口服6周)。在第8周,F和FT组的大鼠开始66% 果糖饮食以诱导高胰岛素血症和高血压。在接下来的4周内,每周测量血浆胰岛素,血浆甘油三酸酯和收缩压。逆转方案: 在一项单独的研究中,使用8周治疗的FH大鼠及其年龄匹配的对照组来检查米贝拉地对逆转果糖诱导的高胰岛素血症和高血压的作用。
    结果 : F组表现为高胰岛素血症 (3.2 +/- 0.1 vs. C 2.3 +/- 0.07 ng/ml,P <0.05),高血压 (148 +/- 3 vs. C 121 +/- 1 mmHg,P <0.002) 和甘油三酯水平升高 (5.4 +/- 0.8 vs. C 1.6 +/- 0.3 mM,P <0.05)。慢性米贝拉地尔治疗可防止高胰岛素血症 (1.6 +/- 0.08 ng/ml,P <0.004 vs. F) 和高血压 (123 +/- 1 mmHg。P <0.001 vs. F) 的发展,并减轻高甘油三酯血症的发展。在逆转研究中,米贝拉地尔治疗逆转了FH大鼠高胰岛素血症,高甘油三酯血症和BP升高的发展。治疗不会影响任何组的血浆葡萄糖水平 (预防或逆转)。
    结论 : 钙拮抗剂mibefradil的长期治疗都可以预防和逆转FH大鼠的高胰岛素血症,高甘油三酯血症和高血压。这些数据表明mibefradil在高胰岛素血症和胰岛素抵抗状态下对碳水化合物和脂质代谢的有益作用。

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