• 【来自大疱性脱血脂的渗出液中的纤维蛋白原/纤维蛋白降解产物。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Mortensen T,Clemmensen I,Søndergaard J
    BACKGROUND & AIMS: Inflammatory exudates from 10 patients with bullous skin diseases were analysed by immunochemical techniques including crossed immunoelectrophoresis. The results were compared with those obtained in fluid from suction bullae obtained in normal skin in 13 control subjects and synovial fluid from 20 patients with rheumatoid arthritis. Abnormal fibrinogen degradation products identical with those found in synovial fluid from patients with rheumatoid arthritis were detected in exudates from each of the patients with bullous dermatoses, whereas significantly smaller amounts of fibrinogen antigenic material were detected in fluid obtained by suction. The fibrinogen antigenic material demonstrated in exudates from pathological bullae, immunochemically similar to that found in rheumatoid synovial fluid, indicates that the presence of these products reflects the more general features of an inflammatory exudate.

    背景与目标: 通过免疫化学技术(包括交叉免疫电泳)分析了10位大疱性皮肤病患者的炎性渗出液。将结果与13例正常受试者从正常皮肤中获得的抽吸大疱中的液体以及20例类风湿性关节炎患者的滑液中获得的结果进行了比较。在每个大疱性皮肤病患者的渗出物中检测到与类风湿性关节炎患者滑液中发现的纤维蛋白原异常降解产物相同,而在通过抽吸获得的液体中检测到的纤维蛋白原抗原物质含量明显降低。病理性大疱渗出液中显示的纤维蛋白原抗原物质在免疫化学上与类风湿滑液中发现的相似,表明这些产物的存在反映了炎性渗出物的更一般特征。

  • 【正常和压力心肌中26S蛋白酶体系统对蛋白质的降解作用。】 复制标题 收藏 收藏
    DOI:10.1089/ars.2006.8.1677 复制DOI
    作者列表:Gomes AV,Zong C,Ping P
    BACKGROUND & AIMS: :The 26S proteasome is a multicatalytic threonine protease complex responsible for degradation of the majority of proteins in eukaryotic cells. In the last two decades, the ubiquitin proteasome system (UPS) has been increasingly recognized as an integral component in numerous biologic processes including cell proliferation, adaptation to stress, and cell death. The turnover of intracellular proteins inevitably affects the contributions of these molecules to cellular networks and pathways in any given tissue or organ, including the myocardium. Perturbations in the protein-degradation process have been shown to affect protein turnover and thereby affect the cardiac cell functions that these molecules are designated to carry out, engendering diseased cardiac phenotypes. Recent studies have implicated the role of proteasomes in stressed cardiac phenotypes including postischemia-reperfusion injury and cardiac remodeling (e.g., heart failure). The 26S proteasomes also appear to be susceptible to modulation by stresses (e.g., reactive oxygen species). This review focuses on roles of the 26S proteasome system in protein degradation; it provides an overview of the progress made in cardiac proteasome research as well as a discussion of recent controversies regarding the UPS system in diseased cardiac phenotypes.
    背景与目标: :26S蛋白酶体是一种多催化苏氨酸蛋白酶复合物,负责真核细胞中大多数蛋白质的降解。在过去的二十年中,泛素蛋白酶体系统(UPS)被越来越多地视为许多生物学过程中不可或缺的组成部分,包括细胞增殖,适应压力和细胞死亡。细胞内蛋白质的周转不可避免地会影响这些分子对任何给定组织或器官(包括心肌)中细胞网络和通路的贡献。已经证明蛋白质降解过程中的扰动会影响蛋白质更新,从而影响这些分子被指定执行的心脏细胞功能,从而引起患病的心脏表型。最近的研究暗示蛋白酶体在紧张的心脏表型中的作用,包括缺血后再灌注损伤和心脏重塑(例如心力衰竭)。 26S蛋白酶体似乎也容易受到压力(例如活性氧)的调节。这篇综述着重于26S蛋白酶体系统在蛋白质降解中的作用。它概述了心脏蛋白酶体研究的进展,并讨论了有关患病心脏表型的UPS系统的最新争议。
  • 【使用与I型胶原C端肽的8个氨基酸序列的异构化形式反应的抗体测量血清中的骨降解产物。】 复制标题 收藏 收藏
    DOI:10.1359/jbmr.1997.12.7.1028 复制DOI
    作者列表:Bonde M,Garnero P,Fledelius C,Qvist P,Delmas PD,Christiansen C
    BACKGROUND & AIMS: An enzyme-linked immunosorbent assay for measuring type I collagen degradation products in serum (S-ELISA) was developed. The assay uses a high affinity polyclonal antibody which reacts with an isomerized form of an 8 amino acid sequence of the C-telopeptides of type I collagen (EKAHD-beta-GGR). Cross-reactivity to a nonisomerized synthetic peptide form of the 8 amino acid sequence is less than 0.2%. Values obtained in a group of premenopausal women (age, 33.3 +/- 3.11 years) were 69 +/- 24 ng/ml(n = 22). In a group of early postmenopausal women (age, 51.8 +/- 1.88 years) values obtained were 125 +/- 43 ng/ml (n = 46), which represents an increase of 81% (p < 0.001). Values found in untreated patients with Paget's disease were 234 +/- 95 ng/ml (n = 15), and for primary hyperparathyroidism we found 335 +/- 82 ng/ml (n = 10). Intravenous administration of a bisphosphonate (Pamidronate) to Paget's disease patients for 3 days was reflected in the S-ELISA by a decrease in the values of 55% when compared with values before treatment (n = 15). Following treatment with another bisphosphonate (Alendronate) for 6 months, values were decreased to 48 +/- 19 ng/ml (n = 12), which corresponds to a 62% decrease. Clinical results presented in this context support that the assay is a sensitive and specific index of bone resorption. It may, therefore, prove useful in the follow up of treatment of patients with metabolic bone diseases and in the clinical investigation of osteoporosis.

    背景与目标: 开发了一种用于测定血清中I型胶原降解产物的酶联免疫吸附测定(S-ELISA)。该测定法使用高亲和力的多克隆抗体,该抗体与I型胶原C端肽的8个氨基酸序列的异构化形式(EKAHD-β-GGR)反应。与8个氨基酸序列的非异构化合成肽形式的交叉反应性小于0.2%。一组绝经前妇女(年龄33.3 / 3.11岁)获得的值为69 /-24 ng / ml(n = 22)。在一组绝经后的早期妇女(年龄为51.8 / 1.88岁)中,其值是125 /-43 ng / ml(n = 46),增加了81%(p <0.001)。在未接受治疗的Paget病患者中发现的值为234 /-95 ng / ml(n = 15),对于原发性甲状旁腺功能亢进症,我们发现的值为335 /-82 ng / ml(n = 10)。在S-ELISA中,与治疗前的值相比降低了55%(n = 15),这反映了向Paget病患者静脉注射双膦酸盐(帕米膦酸)3天。在用另一种双膦酸盐(阿仑膦酸盐)治疗6个月后,其值降低至48±19 ng / ml(n = 12),相当于降低了62%。在这种情况下提出的临床结果支持该测定是骨吸收的灵敏和特异性指标。因此,它可能被证明对代谢性骨病患者的后续治疗以及骨质疏松症的临床研究有用。

  • 【紫杉醇和tau的过度表达诱导钙蛋白酶依赖的微管破坏蛋白SCG10的降解。】 复制标题 收藏 收藏
    DOI:10.1016/j.expneurol.2006.05.026 复制DOI
    作者列表:Vega IE,Hamano T,Propost JA,Grenningloh G,Yen SH
    BACKGROUND & AIMS: :Microtubule-stabilizing and -destabilizing proteins play a crucial role in regulating the dynamic instability of microtubules during neuronal development and synaptic transmission. The microtubule-destabilizing protein SCG10 is a neuron-specific protein implicated in neurite outgrowth. The SCG10 protein is significantly reduced in mature neurons, suggesting that its expression is developmentally regulated. In contrast, the microtubule-stabilizing protein tau is expressed in mature neurons and its function is essential for the maintenance of neuronal polarity and neuronal survival. Thus, the establishment and maintenance of neuronal polarity may down-regulate the protein level/function of SCG10. In this report, we show that treatment of PC12 cells and neuroblastoma cells with the microtubule-stabilizing drug Taxol induced a rapid degradation of the SCG10 protein. Consistently, overexpression of tau protein in neuroblastoma cells also induced a reduction in SCG10 protein levels. Calpain inhibitor MDL-28170, but not caspase inhibitors, blocked a significant decrease in SCG10 protein levels. Collectively, these results indicate that tau overexpression and Taxol treatment induced a calpain-dependent degradation of the microtubule-destabilizing protein SCG10. The results provide evidence for the existence of an intracellular mechanism involved in the regulation of SCG10 upon microtubule stabilization.
    背景与目标: :微管稳定蛋白和去稳定蛋白在调节神经元发育和突触传递过程中微管的动态不稳定性中起关键作用。破坏微管的蛋白SCG10是神经元特异性蛋白,与神经突增生有关。 SCG10蛋白在成熟神经元中显着减少,表明其表达受到发育调节。相反,微管稳定蛋白tau在成熟的神经元中表达,其功能对于维持神经元极性和神经元存活至关重要。因此,神经元极性的建立和维持可能下调SCG10的蛋白质水平/功能。在本报告中,我们显示了用微管稳定药物紫杉醇治疗PC12细胞和成神经细胞瘤细胞会诱导SCG10蛋白快速降解。一致地,神经母细胞瘤细胞中tau蛋白的过表达也诱导了SCG10蛋白水平的降低。钙蛋白酶抑制剂MDL-28170而非caspase抑制剂阻止了SCG10蛋白水平的显着降低。总的来说,这些结果表明tau的过度表达和紫杉酚的处理诱导了钙蛋白酶依赖性降解的微管去稳定蛋白SCG10。结果提供了微管稳定后SCG10调控中涉及的细胞内机制的存在的证据。
  • 【降低的强制呼气量与心房颤动的发生率增加有关:马尔默预防项目。】 复制标题 收藏 收藏
    DOI:10.1093/europace/eut255 复制DOI
    作者列表:Johnson LS,Juhlin T,Engström G,Nilsson PM
    BACKGROUND & AIMS: AIMS:Reduced forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) have been associated with increased incidence of cardiovascular diseases. However, whether reduced lung function is also a risk factor for incidence of atrial fibrillation (AF) is still unclear. We aimed to determine whether lung function predicted AF in the Malmö Preventive Project, a large population-based cohort with a long follow-up. METHODS AND RESULTS:The study population consisted of 7674 women and 21 070 men, mean age 44.6 years. The cohort was followed on average for 24.8 years, during which time 2669 patients were hospitalized due to AF. The incidence of AF in relationship to quartiles of FEV1 and FVC and per litre decrease at baseline was determined using a Cox proportional hazards model adjusted for age, height, weight, current smoking status, systolic blood pressure, erythrocyte sedimentation rate, and fasting blood glucose. Forced expiratory volume in one second was inversely related to incidence of AF (per litre reduction in FEV1) hazard ratio (HR): 1.39 [95% confidence interval (CI): 1.16-1.68; P = 0.001] for women, and HR: 1.20 (95% CI: 1.13-1.29; P < 0.0001) for men. Forced vital capacity was also inversely related to incidence of AF (per litre reduction in FVC) HR: 1.20 (95% CI: 1.03-1.41; P = 0.020) for women, and HR: 1.08 (95% CI: 1.02-1.14; P = 0.01) for men. This relationship was consistent in non-smokers as well as smokers, and among individuals younger than the median age of 45.8 years or normotensive subjects. CONCLUSION:Impaired lung function is an independent predictor of AF. This may explain some risk of AF that is currently unaccounted for.
    背景与目标: 目的:一秒钟内减少强制呼气量(FEV1)和强制肺活量(FVC)与心血管疾病的发病率增加相关。但是,肺功能下降是否也是心房颤动(AF)发生的危险因素仍不清楚。我们旨在确定在马尔默预防项目中,肺功能是否能预测房颤,该项目是一项以人群为基础的大型队列研究,需要长期随访。
    方法与结果:研究人群为7674名女性和21 070名男性,平均年龄44.6岁。该队列平均随访了24.8年,在此期间有2669例因AF住院的患者。使用针对年龄,身高,体重,当前吸烟状况,收缩压,红细胞沉降率和空腹血糖调整的Cox比例风险模型,确定与FEV1和FVC四分位数相关的房颤发生率以及基线时每升的下降。一秒钟的强制呼气量与房颤的发生率(每升FEV1减少)成反比(HR):1.39 [95%置信区间(CI):1.16-1.68; P = 0.001](女性)和HR:1.20(95%CI:1.13-1.29; P <0.0001)。强迫肺活量也与AF的发生率成反比(女性每升FVC降低)HR:女性HR:1.20(95%CI:1.03-1.41; P = 0.020); HR:1.08(95%CI:1.02-1.14); P = 0.01)。在非吸烟者和吸烟者中,以及年龄中位数为45.8岁以下或血压正常的受试者之间,这种关系是一致的。
    结论:肺功能受损是房颤的独立预测因子。这可以解释目前尚无法解决的房颤风险。
  • 【结构互补性促进DCAF15介导E7820介导的RBM39降解。】 复制标题 收藏 收藏
    DOI:10.1038/s41589-019-0378-3 复制DOI
    作者列表:Faust TB,Yoon H,Nowak RP,Donovan KA,Li Z,Cai Q,Eleuteri NA,Zhang T,Gray NS,Fischer ES
    BACKGROUND & AIMS: :The investigational drugs E7820, indisulam and tasisulam (aryl-sulfonamides) promote the degradation of the splicing factor RBM39 in a proteasome-dependent mechanism. While the activity critically depends on the cullin RING ligase substrate receptor DCAF15, the molecular details remain elusive. Here we present the cryo-EM structure of the DDB1-DCAF15-DDA1 core ligase complex bound to RBM39 and E7820 at a resolution of 4.4 Å, together with crystal structures of engineered subcomplexes. We show that DCAF15 adopts a new fold stabilized by DDA1, and that extensive protein-protein contacts between the ligase and substrate mitigate low affinity interactions between aryl-sulfonamides and DCAF15. Our data demonstrate how aryl-sulfonamides neo-functionalize a shallow, non-conserved pocket on DCAF15 to selectively bind and degrade RBM39 and the closely related splicing factor RBM23 without the requirement for a high-affinity ligand, which has broad implications for the de novo discovery of molecular glue degraders.
    背景与目标: :研究用药物E7820,靛蓝和tasisulam(芳基磺酰胺类)以蛋白酶体依赖性机制促进剪接因子RBM39的降解。尽管活性主要取决于cullin RING连接酶底物受体DCAF15,但分子的细节仍然难以捉摸。在这里,我们介绍了DBM1-DCAF15-DDA1核心连接酶复合物以BM4.4的分辨率与RBM39和E7820结合的低温电磁结构,以及工程化的复合物的晶体结构。我们显示,DCAF15采用DDA1稳定的新折叠,并且连接酶和底物之间广泛的蛋白质接触减少了芳基磺酰胺与DCAF15之间的低亲和力相互作用。我们的数据表明,芳基磺酰胺如何在DCAF15上新功能化一个浅的,非保守的口袋,以选择性结合并降解RBM39和紧密相关的剪接因子RBM23,而无需高亲和力配体,这对从头开始具有广泛的意义。分子胶降解剂的发现。
  • 【心脏瓣膜手术后高术前血清Syndecan-1(内皮糖萼降解的标志物)和严重急性肾损伤。】 复制标题 收藏 收藏
    DOI:10.3390/jcm9061803 复制DOI
    作者列表:Kim HB,Soh S,Kwak YL,Bae JC,Kang SH,Song JW
    BACKGROUND & AIMS: :Degradation of endothelial glycocalyx (EG) is associated with inflammation and endothelial dysfunction, which may contribute to the development of acute kidney injury (AKI). We investigated the association between a marker of EG degradation and AKI after valvular heart surgery. Serum syndecan-1 concentrations were measured at induction of anesthesia and discontinuation of cardiopulmonary bypass in 250 patients. Severe AKI was defined as Kidney Disease: Improving Global Outcomes Criteria Stage 2 or 3. Severe AKI occurred in 13 patients (5%). Receiver operating characteristic analysis of preoperative syndecan-1 to predict severe AKI showed area under curve of 0.714 (95% confidence interval (CI), 0.575-0.853; p = 0.009). The optimal cut-off value was 90 ng/mL, with a sensitivity of 61.5% and specificity of 78.5%. In multivariable analysis, both preoperative syndecan-1 ≥ 90 ng/mL and Cleveland Clinic Foundation score independently predicted severe AKI. Severe tricuspid regurgitation was more frequent (42.4% vs. 17.8%, p < 0.001), and baseline right ventricular systolic pressure (41 (33-51) mmHg vs. 33 (27-43) mmHg, p = 0.001) and TNF-α (1.85 (1.37-2.43) pg/mL vs. 1.45 (1.14-1.92) pg/mL, p <0.001) were higher in patients with high preoperative syndecan-1. Patients with high preoperative syndecan-1 had longer hospital stay (16 (12-24) days vs. 13 (11-17) days, p = 0.001). In conclusion, a high preoperative syndecan-1 concentration greater than 90 ng/mL was able to predict severe AKI after valvular heart surgery and was associated with prolonged hospitalization.
    背景与目标: :内皮糖萼(EG)的降解与炎症和内皮功能障碍有关,这可能有助于急性肾损伤(AKI)的发展。我们研究了心脏瓣膜手术后EG降解标志物与AKI之间的关联。在250例患者中,在诱导麻醉和停止体外循环时测量了血清syndecan-1的浓度。严重的AKI被定义为肾脏疾病:改善第2阶段或第3阶段的总体结果标准。严重的AKI发生在13例患者中(5%)。术前syndecan-1的接受者操作特征分析可预测严重AKI,显示曲线下面积为0.714(95%置信区间(CI),0.575-0.853; p = 0.009)。最佳临界值为90 ng / mL,灵敏度为61.5%,特异性为78.5%。在多变量分析中,术前syndecan-1≥90 ng / mL和Cleveland Clinic Foundation评分均独立预测严重AKI。严重的三尖瓣关闭不全更为频繁(42.4%vs. 17.8%,p <0.001),基线右室收缩压(41(33-51)mmHg vs. 33(27-43)mmHg,p = 0.001)和TNF-具有高术前syndecan-1的患者的α(1.85(1.37-2.43)pg / mL与1.45(1.14-1.92)pg / mL,p <0.001)更高。术前Syndecan-1高的患者住院时间更长(16(12-24)天,而13(11-17)天,p = 0.001)。总之,术前高浓度syndecan-1大于90 ng / mL能够预测心脏瓣膜手术后的严重AKI并与长期住院相关。
  • 【细胞结合和脂蛋白降解(一)。】 复制标题 收藏 收藏
    DOI:10.5551/jat1994.2.supplement1_s1 复制DOI
    作者列表:Fless GM
    BACKGROUND & AIMS: Lp(a) is an important contributing factor to the development of atherosclerosis, and in structure is similar to LDL. Given the central role of the LDL receptor (LDL-R) in the metabolism of LDL, we felt that a study of the binding and degradation of Lp(a) facilitated by the LDL-R of human monocyte derived macrophages (HMDM) would be of value in understanding its pathological nature. In this study we compared equimolar amounts of Lp(a) and LDL and found that nearly equal amounts of Lp(a) and LDL bound to the LDL-R of HMDM at 4 degrees C, however the affinity of both lipoproteins was much lower than has been observed for the LDL-R of fibroblasts, being 0.80 muM for Lp(a) and 0.23 muM for LDL. The binding of Lp(a) to HMDM could be competed by 63% with a 50-fold excess of LDL. Degradation of Lp(a) at 37 degree C, unlike 4 degrees C binding, was mainly nonspecific (75% of total Lp(a) degradation) and when compared on an equimolar basis, nearly 6 times more LDL than Lp(a) was processed by the LDL-R pathway in 5 hr. Lower degradation of Lp(a) appears to be the result of lower binding at 37 degree C and a lower degradation rate when compared to LDL. It was not caused by increased intracellular accumulation or retroendocytosis. Degradation of both lipoproteins was only modestly affected by up and down regulation of the LDL-R. Because the binding of LDL at 4 degrees C and degradation at 37 degree C is mainly LDL-R specific, whereas only the 4 degree C binding of Lp(a) is so, suggests that the poor LDL-R dependent degradation of Lp(a) at 37 degree C is caused by a conformational change that is inducted in Lp(a) upon lowering the temperature to 4 degree C which allows better recognition of Lp(a) by the HMDM LDL-R.

    背景与目标: Lp(a)是导致动脉粥样硬化发展的重要因素,其结构类似于LDL。鉴于LDL受体(LDL-R)在LDL代谢中的核心作用,我们认为对人类单核细胞衍生巨噬细胞(HMDM)的LDL-R促进Lp(a)结合和降解的研究将是了解其病理本质的价值。在这项研究中,我们比较了等摩尔量的Lp(a)和LDL,发现在4摄氏度下,几乎等量的Lp(a)和LDL与HMDM的LDL-R结合,但是两种脂蛋白的亲和力都远低于已经观察到成纤维细胞的LDL-R,Lp(a)为0.80μM,LDL为0.23μM。 Lp(a)与HMDM的结合可以与63%的LDL竞争50%。与4摄氏度的结合不同,Lp(a)在37摄氏度下的降解主要是非特异性的(占总Lp(a)降解的75%),当以等摩尔量进行比较时,其LDL比Lp(a)高近6倍在5小时内被LDL-R途径处理。与LDL相比,Lp(a)的较低降解似乎是在37摄氏度下较低的结合力和较低的降解速率的结果。它不是由增加的细胞内积累或内吞作用引起的。两种脂蛋白的降解仅受LDL-R上调和下调的影响。因为LDL在4摄氏度的结合和37摄氏度的降解主要是LDL-R特异性的,而Lp(a)的4摄氏度的结合是LDL-R特异性的,这表明Lp(a)依赖LDL-R的降解较差)在37摄氏度时是由于将温度降低到4摄氏度时在Lp(a)中引起的构象变化而引起的,这使得HMDM LDL-R可以更好地识别Lp(a)。

  • 【缺氧相关因子,一种新型的E3泛素连接酶,结合并泛素化缺氧诱导因子1alpha,导致其氧依赖性降解。】 复制标题 收藏 收藏
    DOI:10.1128/MCB.00773-08 复制DOI
    作者列表:Koh MY,Darnay BG,Powis G
    BACKGROUND & AIMS: :The hypoxia-inducible factor 1alpha (HIF-1alpha) is the master regulator of the cellular response to hypoxia. A key regulator of HIF-1alpha is von Hippel-Lindau protein (pVHL), which mediates the oxygen-dependent, proteasomal degradation of HIF-1alpha in normoxia. Here, we describe a new regulator of HIF-1alpha, the hypoxia-associated factor (HAF), a novel E3-ubiquitin ligase that binds HIF-1alpha leading to its proteasome-dependent degradation irrespective of cellular oxygen tension. HAF, a protein expressed in proliferating cells, binds and ubiquitinates HIF-1alpha in vitro, and both binding and E3 ligase activity are mediated by HAF amino acids 654 to 800. Furthermore, HAF overexpression decreases HIF-1alpha levels in normoxia and hypoxia in both pVHL-competent and -deficient cells, whereas HAF knockdown increases HIF-1alpha levels in normoxia, hypoxia, and under epidermal growth factor stimulation. In contrast, HIF-2alpha is not regulated by HAF. In vivo, tumor xenografts from cells overexpressing HAF show decreased levels of HIF-1alpha accompanied by decreased tumor growth and angiogenesis. Therefore, HAF is the key mediator of a new HIF-1alpha-specific degradation pathway that degrades HIF-1alpha through a new, oxygen-independent mechanism.
    背景与目标: :缺氧诱导因子1alpha(HIF-1alpha)是细胞对缺氧反应的主要调节因子。 HIF-1alpha的关键调控因子是von Hippel-Lindau蛋白(pVHL),它介导常氧条件下HIF-1alpha的氧依赖性蛋白酶体降解。在这里,我们描述了一种新的HIF-1alpha调节因子,缺氧相关因子(HAF),一种新型的E3-泛素连接酶,它结合HIF-1alpha导致其蛋白酶体依赖性降解,而与细胞氧张力无关。 HAF是一种在增殖细胞中表达的蛋白质,在体外结合并泛素化HIF-1alpha,结合和E3连接酶活性均由HAF氨基酸654-800介导。此外,HAF的过表达降低了正常氧和低氧状态下HIF-1alpha的水平。具有pVHL能力的细胞和缺陷型细胞,而HAF敲低会增加常氧,低氧和表皮生长因子刺激下的HIF-1alpha水平。相反,HIF-2alpha不受HAF调控。在体内,来自过表达HAF的细胞的异种移植物显示HIF-1alpha的水平降低,并伴随着肿瘤的生长和血管生成的降低。因此,HAF是新的HIF-1alpha特异性降解途径的关键介体,该途径通过新的,与氧无关的机制降解HIF-1alpha。
  • 【半纤维素的高温降解,这是生物能源和其他增值产品生产中的关键原料。】 复制标题 收藏 收藏
    DOI:10.1128/AEM.02296-19 复制DOI
    作者列表:Cann I,Pereira GV,Abdel-Hamid AM,Kim H,Wefers D,Kayang BB,Kanai T,Sato T,Bernardi RC,Atomi H,Mackie RI
    BACKGROUND & AIMS: :Renewable fuels have gained importance as the world moves toward diversifying its energy portfolio. A critical step in the biomass-to-bioenergy initiative is deconstruction of plant cell wall polysaccharides to their unit sugars for subsequent fermentation to fuels. To acquire carbon and energy for their metabolic processes, diverse microorganisms have evolved genes encoding enzymes that depolymerize polysaccharides to their carbon/energy-rich building blocks. The microbial enzymes mostly target the energy present in cellulose, hemicellulose, and pectin, three major forms of energy storage in plants. In the effort to develop bioenergy as an alternative to fossil fuel, a common strategy is to harness microbial enzymes to hydrolyze cellulose to glucose for fermentation to fuels. However, the conversion of plant biomass to renewable fuels will require both cellulose and hemicellulose, the two largest components of the plant cell wall, as feedstock to improve economic feasibility. Here, we explore the enzymes and strategies evolved by two well-studied bacteria to depolymerize the hemicelluloses xylan/arabinoxylan and mannan. The sets of enzymes, in addition to their applications in biofuels and value-added chemical production, have utility in animal feed enzymes, a rapidly developing industry with potential to minimize adverse impacts of animal agriculture on the environment.
    背景与目标: :随着世界朝着多样化能源组合的方向发展,可再生燃料变得越来越重要。生物质转化为生物能的关键步骤是将植物细胞壁多糖解构成其单位糖,然后发酵为燃料。为了获得碳和能量用于其代谢过程,各种各样的微生物已经进化出了编码酶的基因,该酶将多糖解聚成其碳/能量丰富的结构单元。微生物酶主要针对纤维素,半纤维素和果胶中存在的能量,这是植物中能量存储的三种主要形式。在努力开发生物能源替代化石燃料方面,一种常见的策略是利用微生物酶将纤维素水解为葡萄糖,然后发酵为燃料。然而,植物生物质向可再生燃料的转化将需要纤维素和半纤维素(植物细胞壁的两个最大成分)作为原料,以提高经济可行性。在这里,我们探索由两种经过充分研究的细菌进化出的酶和策略,以使半纤维素木聚糖/阿拉伯木聚糖和甘露聚糖解聚。这套酶除了在生物燃料和增值化学产品中的应用外,还可以在动物饲料酶中使用。动物饲料酶是一个快速发展的行业,具有将动物农业对环境的不利影响降至最低的潜力。
  • 【SCFβ-TrCP介导的TOP2β降解可响应靶向拓扑异构酶II的化学治疗药物促进癌细胞存活。】 复制标题 收藏 收藏
    DOI:10.1038/s41389-020-0196-1 复制DOI
    作者列表:Shu J,Cui D,Ma Y,Xiong X,Sun Y,Zhao Y
    BACKGROUND & AIMS: :Topoisomerase II (TOP2)-targeting anticancer chemotherapeutic drugs, termed TOP2 poisons, are widely used and effective in the clinic by stabilizing TOP2-DNA covalent complexes to induce DNA double-strand breaks (DSBs) and ultimately, cause cell death. The stabilized TOP2-DNA complex is known to be degraded by proteasome, whereas the underlying mechanism for instant TOP2β degradation in response to TOP2 poisons and the subsequent biological consequence remain elusive. Here, we reported that TOP2 poison-induced TOP2β degradation is mediated by SCFβ-TrCP ubiquitin ligase. Specifically, DNA damage signal, triggered by teniposide (VM-26) treatment, activates ATM, cooperating with CK1 to phosphorylate TOP2β on Ser1134 and Ser1130, respectively, in a canonical degron motif to facilitate β-TrCP binding and subsequent degradation. Inactivation of ATM, CK1 or SCFβ-TrCP by small molecular inhibitors or genetic knockdown/knockout abrogates TOP2β degradation. Biologically, blockage of TOP2β degradation in combination with VM-26 treatment impairs DNA damage response and repair, leading to an accelerated cell death via apoptosis. Thus, it appears that TOP2β degradation is a cellular defensive mechanism to facilitate the exposure of DSBs to trigger DNA damage response and repair. Collectively, our findings reveal a new strategy to improve the efficacy of TOP2 poisons in combination with small-molecule inhibitors against TOP2β degradation.
    背景与目标: 靶向拓扑异构酶II(TOP2)的抗癌化学治疗药物,称为TOP2毒物,通过稳定TOP2-DNA共价复合物诱导DNA双链断裂(DSB)并最终导致细胞死亡,在临床上得到了广泛使用和有效。已知稳定的TOP2-DNA复合物可被蛋白酶体降解,而响应TOP2毒物而引起的即时TOP2β降解的基本机制以及随后的生物学后果仍然难以捉摸。在这里,我们报道了TOP2毒物诱导的TOP2β降解是由SCFβ-TrCP泛素连接酶介导的。具体而言,由替尼泊苷(VM-26)处理触发的DNA损伤信号激活ATM,与CK1协同作用以规范化的德格伦基序磷酸化Ser1134和Ser1130上的TOP2β,以促进β-TrCP结合和随后的降解。小分子抑制剂使ATM,CK1或SCFβ-TrCP失活或基因敲除/敲除消除了TOP2β的降解。从生物学上讲,TOP2β降解的阻断与VM-26治疗相结合会损害DNA损伤反应和修复,从而导致细胞通过凋亡加速死亡。因此,看来TOP2β降解是促进DSB暴露以触发DNA损伤反应和修复的细胞防御机制。总体而言,我们的发现揭示了一种新的策略,可与小分子抑制剂联合使用以提高TOP2毒物的功效,以对抗TOP2β降解。
  • 【生物堆肥改良剂对土壤中三唑类杀菌剂降解的影响。】 复制标题 收藏 收藏
    DOI:10.1007/s00128-008-9536-0 复制DOI
    作者列表:Singh N,Dureja P
    BACKGROUND & AIMS: :Soil amendments play an important role in management of pesticide residues. Present study reports the effect of biocompost-amendment on degradation of penconazole and propiconazole (triazole fungicides) in a sandy loam soil under flooded and nonflooded (60% water holding capacity) conditions. Penconazole degraded at faster rate than propiconazole. Both the fungicides were found to be more persistent in flooded soil than nonflooded soil, but application of biocompost at 2.5% and 5.0% levels enhanced their degradation under both moisture regimes.
    背景与目标: :土壤改良剂在农药残留管理中起着重要作用。本研究报告了在堆肥和未淹没(持水量为60%)条件下,沙质壤土中生物堆肥改良剂对戊烯唑和丙环唑(三唑类杀真菌剂)降解的影响。戊康唑的降解速率比丙康唑更快。发现两种杀真菌剂在淹没土壤中比未淹没土壤更具持久性,但是在两种水分制度下,分别以2.5%和5.0%的水平施用生物堆肥可提高其降解能力。
  • 【S-1-丙烯半胱氨酸通过自噬介导的蛋白质降解来调节免疫应答。】 复制标题 收藏 收藏
    DOI:10.3892/etm.2019.8392 复制DOI
    作者列表:Suzuki JI,Miki S,Ushijima M,Kodera Y
    BACKGROUND & AIMS: :Autophagy is a key event in cellular recycling processes due to its involvement in the intracellular degradation of proteins. It has been demonstrated that S-1-propenylcysteine (S1PC), a characteristic sulfur compound in aged garlic extract, induces the activation of autophagy. S1PC degrades the adaptor protein myeloid differentiation response protein 88 (MyD88) of downstream of Toll-like receptor (TLR) by activating autophagy in vitro and in vivo. The degradation of MyD88 inhibits the TLR signaling pathway, including the phosphorylation of interleukin 1 receptor associated kinase 4 (IRAK4) and nuclear factor (NF)-κB p65 in vitro, and eventually leads to the inhibition of interleukin (IL)-6 production in vitro and C-C motif chemokine ligand 2 (Ccl2) mRNA expression in vivo. S1PC also increases the level of intestinal immunoglobulin A (IgA) and the number of IgA-producing cells in Peyer's patches in vivo. In addition, S1PC triggers the mRNA expression of X-box binding protein 1 (Xbp1), an inducer of IgA-producing cell differentiation via the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and the degradation of paired box protein 5 (Pax5), a suppressor of Xbp1 mRNA expression. The present review summarizes the mechanisms through which the activation of autophagy by S1PC modulates the immune response.
    背景与目标: 自噬是细胞再生过程中的关键事件,因为它参与了蛋白质的细胞内降解。已经证明,老化的大蒜提取物中的特征性硫化合物S-1-丙烯基半胱氨酸(S1PC)诱导自噬的激活。 S1PC通过在体内和体外激活自噬来降解Toll样受体(TLR)下游的衔接蛋白髓样分化反应蛋白88(MyD88)。 MyD88的降解会抑制TLR信号传导途径,包括体外的白介素1受体相关激酶4(IRAK4)和核因子(NF)-κBp65的磷酸化,最终导致抑制白介素1(IL)-6的产生。体外和CC基序趋化因子配体2(Ccl2)mRNA的体内表达。 S1PC还可以提高体内Peyer斑块中肠道免疫球蛋白A(IgA)的水平和产生IgA的细胞的数量。此外,S1PC触发X-box结合蛋白1(Xbp1)的mRNA表达,X-box结合蛋白1通过细胞外信号调节激酶(ERK)1/2的磷酸化和配对盒蛋白5的降解而诱导产生IgA的细胞分化。 (Pax5),Xbp1 mRNA表达的抑制剂。本综述总结了S1PC激活自噬调节免疫反应的机制。
  • 【富含3'AU的序列促进了poly(A)的去除和c-fos mRNA的降解。】 复制标题 收藏 收藏
    DOI:10.1038/336396a0 复制DOI
    作者列表:Wilson T,Treisman R
    BACKGROUND & AIMS: :The c-fos proto-oncogene provides a good system to study the processes underlying messenger RNA degradation. After growth factor stimulation of susceptible cells, the c-fos transcription rate transiently increases from a low basal level by as much as 50-fold, producing a large amount of exceedingly unstable c-fos mRNA that is rapidly degraded. Here, we investigate the c-fos mRNA degradation process, and find that: (1) ongoing translation of the c-fos mRNA itself is required for its degradation; (2) after synthesis, the mRNA poly(A) tail is rapidly removed, in a translation-dependent manner, leading to accumulation of apparently deadenylated RNA; (3) deletion or replacement of an AU-rich sequence at the mRNA 3' end significantly stabilizes the mRNA; (4) deletion of the 3' AU-rich sequences dramatically slows the poly(A) shortening rate. These results suggest that the 3' AU-rich sequences act to destabilize the mRNA by directing rapid removal of the mRNA poly(A) tract.
    背景与目标: :c-fos原癌基因提供了一个很好的系统来研究信使RNA降解的基础过程。在易感细胞的生长因子刺激后,c-fos转录速率从低基础水平瞬时增加了多达50倍,从而产生了大量极其不稳定的c-fos mRNA,并迅速降解。在这里,我们研究了c-fos mRNA的降解过程,发现:(1)c-fos mRNA本身的持续翻译对其降解是必需的; (2)合成后,以翻译依赖性方式快速去除mRNA poly(A)尾巴,导致明显的去腺苷酸化RNA积累。 (3)在mRNA 3'末端缺失或替换富含AU的序列可显着稳定mRNA; (4)删除富含3'AU的序列会大大减慢poly(A)的缩短速度。这些结果表明,富含3'AU的序列通过指导快速去除mRNA poly(A)束而使mRNA不稳定。
  • 【喜树碱诱导的DDX5降解增加了骨肉瘤的喜树碱抗性。】 复制标题 收藏 收藏
    DOI:10.1016/j.yexcr.2020.112148 复制DOI
    作者列表:Zhao X,Bao M,Zhang F,Wang W
    BACKGROUND & AIMS: :Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. Unfortunately, chemo-resistance is a huge obstacle in the treatment of OS. However, the underlying molecular mechanisms of OS chemo-resistance still remain unknown. Here we reported that the resistance to camptothecin (cpt) therapy was driven by degradation of DDX5. DDX5 knockdown decreased cell death and DNA damage and recovered cell proliferation in cpt treated 143B cells. Furthermore, we found that DDX5 bound to NONO, a kind of DNA repairing protein, and regulated NONO functions. Our data verified that cpt-induced degradation of DDX5 following by breaking down the protein bound of NONO, which participated in the resistance of cpt. In the summary, according to our results, DDX5 might be a potential therapeutic target for improving clinical outcomes of cpt in OS.
    背景与目标: :骨肉瘤(OS)是儿童和青少年中最常见的原发性恶性骨肿瘤。不幸的是,耐化学性是OS治疗的巨大障碍。但是,OS化学抗性的潜在分子机制仍然是未知的。在这里,我们报道了喜树碱(cpt)治疗的耐药性是由DDX5降解引起的。 DDX5组合物降低了cpt处理的143B细胞的细胞死亡和DNA损伤,并恢复了细胞增殖。此外,我们发现DDX5与NONO(一种DNA修复蛋白)结合,并调节NONO功能。我们的数据证实了cpt诱导的DDX5降解是通过破坏NONO的蛋白质结合而引起的,NONO参与了cpt的抗性。总之,根据我们的结果,DDX5可能是改善OS中cpt临床结果的潜在治疗靶标。

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