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Myeloperoxidase and Septic Conditions Disrupt Sphingolipid Homeostasis in Murine Brain Capillaries In Vivo and Immortalized Human Brain Endothelial Cells In Vitro.


  • 影响因子:4.1830
  • DOI:10.3390/ijms21031143
  • 作者列表:"Goeritzer M","Bernhart E","Plastira I","Reicher H","Leopold C","Eichmann TO","Rechberger G","Madreiter-Sokolowski CT","Prasch J","Eller P","Graier WF","Kratky D","Malle E","Sattler W
  • 发表时间:2020-02-09

:During inflammation, activated leukocytes release cytotoxic mediators that compromise blood-brain barrier (BBB) function. Under inflammatory conditions, myeloperoxidase (MPO) is critically involved in inflicting BBB damage. We used genetic and pharmacological approaches to investigate whether MPO induces aberrant lipid homeostasis at the BBB in a murine endotoxemia model. To corroborate findings in a human system we studied the impact of sera from sepsis and non-sepsis patients on brain endothelial cells (hCMEC/D3). In response to endotoxin, the fatty acid, ceramide, and sphingomyelin content of isolated mouse brain capillaries dropped and barrier dysfunction occurred. In mice, genetic deficiency or pharmacological inhibition of MPO abolished these alterations. Studies in metabolic cages revealed increased physical activity and less pronounced sickness behavior of MPO-/- compared to wild-type mice in response to sepsis. In hCMEC/D3 cells, exogenous tumor necrosis factor α (TNFα) potently regulated gene expression of pro-inflammatory cytokines and a set of genes involved in sphingolipid (SL) homeostasis. Notably, treatment of hCMEC/D3 cells with sera from septic patients reduced cellular ceramide concentrations and induced barrier and mitochondrial dysfunction. In summary, our in vivo and in vitro data revealed that inflammatory mediators including MPO, TNFα induce dysfunctional SL homeostasis in brain endothelial cells. Genetic and pharmacological inhibition of MPO attenuated endotoxin-induced alterations in SL homeostasis in vivo, highlighting the potential role of MPO as drug target to treat inflammation-induced brain dysfunction.


: 炎症过程中,活化的白细胞释放细胞毒性介质,损害血脑屏障 (BBB) 功能。在炎症条件下,髓过氧化物酶 (MPO) 严重参与造成 BBB 损伤。我们采用遗传和药理学方法研究 MPO 是否在小鼠内毒素血症模型的 BBB 诱导异常的脂质稳态。为了证实在人类系统中的发现,我们研究了脓毒症和非脓毒症患者血清对大脑内皮细胞 (hCMEC/D3) 的影响。在内毒素作用下,小鼠离体脑毛细血管的脂肪酸、神经酰胺和鞘磷脂含量下降,屏障功能障碍。在小鼠中,MPO 的遗传缺陷或药理学抑制消除了这些改变。代谢笼中的研究发现,与野生型小鼠相比,MPO-/-对脓毒症的反应增加了体力活动和不太明显的疾病行为。在 hCMEC/D3 细胞中,外源性肿瘤坏死因子 α (tnf α) 强烈调控促炎细胞因子的基因表达和一组参与鞘脂 (SL) 稳态的基因。值得注意的是,用脓毒症患者血清处理 hCMEC/D3 细胞可降低细胞神经酰胺浓度,诱导屏障和线粒体功能障碍。总之,我们的体内和体外数据揭示了炎症介质包括 MPO 、 tnf α 诱导大脑内皮细胞功能失调的 SL 稳态。MPO 的遗传和药理学抑制减弱了内毒素诱导的体内 SL 稳态的改变,突出了 MPO 作为治疗炎症诱导的脑功能障碍的药物靶点的潜在作用。



作者列表:["Galm, Brandon P.","Buckless, Colleen","Swearingen, Brooke","Torriani, Martin","Klibanski, Anne","Bredella, Miriam A.","Tritos, Nicholas A."]

METHODS:Purpose Given the paucity of reliable predictors of tumor recurrence, progression, or response to somatostatin receptor ligand (SRL) therapy in acromegaly, we attempted to determine whether preoperative MR image texture was predictive of these clinical outcomes. We also determined whether image texture could differentiate somatotroph adenomas from non-functioning pituitary adenomas (NFPAs). Methods We performed a retrospective study of patients with acromegaly due to a macroadenoma who underwent transsphenoidal surgery at our institution between 2007 and 2015. Clinical data were extracted from electronic medical records. MRI texture analysis was performed on preoperative non-enhanced T1-weighted images using ImageJ (NIH). Logistic and Cox models were used to determine if image texture parameters predicted outcomes. Results Eighty-nine patients had texture parameters measured, which were compared to that of NFPAs, while 64 of these patients had follow-up and were included in the remainder of analyses. Minimum pixel intensity, skewness, and kurtosis were significantly different in somatotroph adenomas versus NFPAs (area under the receiver operating characteristic curve, 0.7771, for kurtosis). Furthermore, those with a maximum pixel intensity above the median had an increased odds of IGF-I normalization on SRL therapy (OR 5.96, 95% CI 1.33–26.66), which persisted after adjusting for several potential predictors of response. Image texture did not predict tumor recurrence or progression. Conclusion Our data suggest that MRI texture analysis can distinguish NFPAs from somatotroph macroadenomas with good diagnostic accuracy and can predict normalization of IGF-I with SRL therapy.

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翻译标题与摘要 下载文献
作者列表:["Xiong Y","Tang Y","Fan F","Zeng Y","Li C","Zhou G","Hu Z","Zhang L","Liu Z"]

METHODS::Growth hormone-secreting pituitary adenoma (GHPA), a benign endocrine tumor located in the base of the skull, results in acromegaly. In addition to the mass effect of the tumor itself in the sellar region, GHPA can lead to the overgrowth of almost every organ. Previous findings indicated that the processes underlying acromegaly were partly attributable to hyperactivity of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis. However, the mechanisms driving this syndrome remains largely unknown. Additionally, the roles of GHPA-derived exosomes, which contain functional microRNAs and proteins that manipulate target cell proliferation and differentiation in distal extremities, are also unknown. In this study, we demonstrated that GHPA exosomes promote bone formation in vitro and trabecula number in vivo. The mechanism of increased trabecula formation may be attributable to GHPA exosome-induced osteoblast proliferation via increased cell viability and DNA replication. We further discovered that exosomal hsa-miR-21-5p plays a distinct role from the GH/IGF-1 axis in these processes. Accordingly, the results of this study provide a novel mechanism whereby GHPA influences distal extremities and a new perspective for treating GHPA.

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翻译标题与摘要 下载文献
作者列表:["Arlien-Søborg MC","Grøndahl C","Bæk A","Dal J","Madsen M","Høgild ML","Pedersen SB","Bjerre M","Jørgensen JOL"]

METHODS:BACKGROUND:Fibroblast growth factor 21 (FGF21) is a circulating hormone with pleiotropic metabolic effects, which is inactivated by fibroblast activation protein (FAP). Data regarding interaction between FGF21, FAP, and growth hormone (GH) are limited, but it is noteworthy that collagens are also FAP substrates, since GH potently stimulates collagen turnover. AIM:To measure circulating FGF21 components, including FAP, in patients with acromegaly before and after disease control. METHODS:Eighteen patients with active acromegaly were studied at the time of diagnosis and ≥ 6 months after disease control by either surgery or medical treatment. Serum levels of total and active FGF21, β-klotho, FAP, and collagen turnover markers were measured by immunoassays. Expression of putative FGF21-dependent genes were measured in adipose tissue by reverse transcriptase-polymerase chain reaction, body composition assessed by dual-energy x-ray absorptiometry scan, and insulin sensitivity estimated with homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS:Total FGF21, active FGF21 and β-klotho remained unchanged. Insulin sensitivity and body fat mass increased after disease control but neither correlated with active FGF21. Expression of FGF21-dependent genes did not change after treatment. FAP levels (µg/L) were markedly reduced after treatment [105.6 ± 29.4 vs 62.2 ± 32.4, P < 0.000]. Collagen turnover markers also declined significantly after treatment and ΔFAP correlated positively with ΔProcollagen Type I (P < 0.000) and Type III (P < 0.000). CONCLUSION:1) Circulating FGF21 and β-klotho do not change in response to acromegaly treatment, 2) FAP concentrations in serum decrease after disease control and correlate positively with collagen turnover markers, and 3) FAP is a hitherto unrecognized GH target linked to collagen turnover. CLINICAL TRIALS REGISTRATION:NCT00647179.