scholarly journals Examining potential side effects of therapeutic hypothermia in experimental intracerebral hemorrhage

2016 ◽  
Vol 37 (8) ◽  
pp. 2975-2986 ◽  
Author(s):  
Shannon Wowk ◽  
Kelly J Fagan ◽  
Yonglie Ma ◽  
Helen Nichol ◽  
Frederick Colbourne
Keyword(s):  
Intracerebral Hemorrhage ◽  
Therapeutic Hypothermia ◽  
Fold Increase ◽  
Inflammatory Cells ◽  
Heme Iron ◽  
Whole Body ◽  
Hematoma Volume ◽  
Post Injury ◽  
X Ray ◽  
Non Heme Iron

Studies treating intracerebral hemorrhage (ICH) with therapeutic hypothermia (TH) have shown inconsistent benefits. We hypothesized that TH’s anti-inflammatory effects may be responsible as inflammatory cells are essential for removing degrading erythrocytes. Here, we subjected rats to a collagenase-induced striatal ICH followed by whole-body TH (∼33℃ for 11–72 h) or normothermia. We used X-ray fluorescence imaging to spatially quantify total and peri-hematoma iron three days post-injury. At three and seven days, we measured non-heme iron levels. Finally, hematoma volume was quantified on one, three, and seven days. In the injured hemisphere, total iron levels were elevated ( p < 0.001) with iron increasing in the peri-hematoma region ( p = 0.007). Non-heme iron increased from three to seven days (p < 0.001). TH had no effect on any measure of iron ( p ≥ 0.479). At one and three days, TH did not affect hematoma volume ( p ≥ 0.264); however, at seven days there was a four-fold increase in hematoma volume in 40% of treated animals ( p = 0.032). Thus, even when TH does not interfere with initial increases in total and non-heme iron or its containment, TH can cause re-bleeding post-treatment. This serious complication could partly account for the intermittent protection previously observed. This also raises serious concerns for clinical usage of TH for ICH.

scholarly journals Anti-inflammatory genes in PBMCs post-spontaneous intracerebral hemorrhage

2021 ◽  
Vol 12 (1) ◽  
pp. 58-66
Author(s):  
Doan Nguyen ◽  
Vi Tran ◽  
Alireza Shirazian ◽  
Cruz Velasco-Gonzalez ◽  
Ifeanyi Iwuchukwu
Keyword(s):  
Intracerebral Hemorrhage ◽  
Negative Correlation ◽  
Mononuclear Cells ◽  
Inflammatory Cells ◽  
Favorable Outcome ◽  
Hospital Length Of Stay ◽  
Spontaneous Intracerebral Hemorrhage ◽  
Hematoma Volume ◽  
Peripheral Blood Mononuclear ◽  
Anti Inflammatory

Abstract Background Neuroinflammation is important in the pathophysiology of spontaneous intracerebral hemorrhage (ICH) and peripheral inflammatory cells play a role in the clinical evolution and outcome. Methodology Blood samples from ICH patients (n = 20) were collected at admission for 5 consecutive days for peripheral blood mononuclear cells (PBMCs). Frozen PBMCs were used for real-time PCR using Taqman probes (NFKB1, SOD1, PPARG, IL10, NFE2L2, and REL) and normalized to GAPDH. Data on hospital length of stay and modified Rankin score (MRS) were collected with 90-day MRS ≤ 3 as favorable outcome. Statistical analysis of clinical characteristics to temporal gene expression from early to delayed timepoints was compared for MRS groups (favorable vs unfavorable) and hematoma volume. Principle findings and results IL10, SOD1, and REL expression were significantly higher at delayed timepoints in PBMCs of ICH patients with favorable outcome. PPARG and REL increased between timepoints in patients with favorable outcome. NFKB1 expression was not sustained, but significantly decreased from higher levels at early onset in patients with unfavorable outcome. IL10 expression showed a negative correlation in patients with high hematoma volume (>30 mL). Conclusions and significance Anti-inflammatory, pro-survival regulators were highly expressed at delayed time points in ICH patients with a favorable outcome, and IL10 expression showed a negative correlation to high hematoma volume.

scholarly journals L-edge X-ray Absorption Spectroscopy of Non-Heme Iron Sites:  Experimental Determination of Differential Orbital Covalency

2003 ◽  
Vol 125 (42) ◽  
pp. 12894-12906 ◽  
Author(s):  
Erik C. Wasinger ◽  
Frank M. F. de Groot ◽  
Britt Hedman ◽  
Keith O. Hodgson ◽  
Edward I. Solomon
Keyword(s):  
Experimental Determination ◽  
Absorption Spectroscopy ◽  
Heme Iron ◽  
X Ray ◽  
Non Heme Iron ◽  
X Ray Absorption

High-intensity training induces EIB in rats through neuron transdifferentiation of adrenal medulla chromaffin cells

2013 ◽  
Vol 304 (9) ◽  
pp. L602-L612 ◽  
Author(s):  
Ruoxi He ◽  
Juntao Feng ◽  
Qiufen Xun ◽  
Qingwu Qin ◽  
Chengping Hu
Keyword(s):  
Adrenal Medulla ◽  
Chromaffin Cells ◽  
Cell Structure ◽  
Fold Increase ◽  
Inflammatory Cells ◽  
Whole Body ◽  
Moderate Intensity ◽  
Sprague Dawley ◽  
Exercise Interventions ◽  
Intensity Training

A high prevalence of exercise-induced bronchoconstriction (EIB) can be found in elite athletes, but the underlying mechanisms remain elusive. Airway responsiveness, NGF and epinephrine (EPI) levels, and chromaffin cell structure in high- (HiTr) and moderate-intensity training (MoTr) rats with or without ovalbumin (OVA) sensitization were measured in a total of 120 male Sprague-Dawley rats. The expression of NGF-associated genes in rat adrenal medulla was tested. Both HiTr and OVA intervention significantly increased airway resistance to aerosolized methacholine measured by whole body plethysmography. HiTr significantly increased inflammatory reaction in the lung with a major increase in peribronchial lymphocyte infiltration, whereas OVA significantly increased the infiltration of various inflammatory cells with an over 10-fold increase in eosinophil level in bronchoalveolar lavage. Both HiTr and OVA intervention upregulated circulating NGF level and peripherin level in adrenal medulla, but downregulated phenylethanolamine N-methyl transferase level in adrenal medulla and circulating EPI level. HiTr + OVA and HiTr + ExhEx (exhaustive exercise) interventions significantly enhanced most of the HiTr effects. The elevated NGF level was significantly associated with neuronal conversion of adrenal medulla chromaffin cells (AMCC). The levels of p-Erk1/2, JMJD3, and Mash1 were significantly increased, but the levels of p-p38 and p-JNK were significantly decreased in adrenal medulla in HiTr and OVA rats. Injection of NGF antiserum and moderate-intensity training reversed these changes observed in HiTr and/or OVA rats. Our study suggests that NGF may play a vital role in the pathogenesis of EIB by inducing neuron transdifferentiation of AMCC via MAPK pathways and subsequently decreasing circulating EPI.

Synthesis, characterization, X-ray molecular structure and catalase-like activity of a non-heme iron complex: Dichloro[N-propanoate-N,N-bis-(2-pyridylmethyl)amine]iron(III)

2006 ◽  
Vol 359 (13) ◽  
pp. 4250-4258 ◽  
Author(s):  
Nakédia M.F. Carvalho ◽  
Adolfo Horn ◽  
Roberto B. Faria ◽  
Adailton J. Bortoluzzi ◽  
Valderes Drago ◽  
...  
Keyword(s):  
Molecular Structure ◽  
Iron Complex ◽  
Heme Iron ◽  
X Ray ◽  
Non Heme Iron

The Serine Protease Tmprss6 Regulates Hepcidin Expression, but Its Loss Does Not Cause Systemic Iron Deficiency In the Fetal and Neonatal Periods

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4258-4258
Author(s):  
Ramsey M. Wehbe ◽  
Rebecca L. Whittlesey ◽  
Nancy C. Andrews ◽  
Karin E. Finberg
Keyword(s):  
Iron Deficiency ◽  
Iron Homeostasis ◽  
Iron Concentration ◽  
Fold Increase ◽  
Heme Iron ◽  
Hepcidin Expression ◽  
Non Heme Iron ◽  
Iron Parameters ◽  
Maternal Iron ◽  
Hepcidin Mrna

Abstract Abstract 4258 Mutations in TMPRSS6 (matriptase-2), a transmembrane serine protease expressed by the liver, result in the clinical phenotype of iron refractory iron deficiency anemia (IRIDA). Additionally, common polymorphisms in TMPRSS6 have been associated with variation in laboratory parameters of iron homeostasis in healthy populations. TMPRSS6 increases iron absorption by reducing expression of the hepatic hormone, hepcidin, via down-regulation of a BMP/SMAD signaling cascade. Hepcidin promotes the internalization and degradation of the duodenal iron transporter, ferroportin, thereby inhibiting iron absorption. Previous studies have demonstrated that adult mice with Tmprss6 deficiency exhibit elevated hepatic hepcidin mRNA levels that are associated with decreased hepatic iron stores. In one study, genetic loss of Tmprss6 was shown to result in significant elevation of hepatic hepcidin expression in mice at birth; however, whether this hepcidin elevation was associated with abnormalities in iron homeostasis was not reported. We therefore asked if the elevated hepcidin levels present in newborn Tmprss6-/- pups correlate with abnormal parameters of iron homeostasis in the fetal or neonatal periods. To answer this question, we intercrossed Tmprss6+/− mice to generate Tmprss6+/+, Tmprss6+/−, and Tmprss6-/- progeny for phenotypic characterization at either gestational day 17.5 (E17.5) or postnatal day 0 (P0). Consistent with prior observations, Tmprss6-/- pups at P0 showed a 4.6-fold increase in hepatic hepcidin mRNA compared to Tmprss6+/+ littermates (p=.006). However, despite this elevation in hepcidin expression, Tmprss6-/- pups were not pale, and they showed no significant differences in body mass or hepatic non-heme iron concentration compared to Tmprss6+/+ and Tmprss6+/− littermates. At E17.5, Tmprss6-/- fetuses showed a 50-fold increase in hepatic hepcidin mRNA compared to Tmprss6+/+ littermates (p=.005). However, Tmprss6-/- fetuses also were not pale, and they showed no significant difference in body mass compared to Tmprss6+/+ and Tmprss6+/− littermates. Surprisingly, hepatic non-heme iron concentration at E17.5 was significantly higher in Tmprss6-/- fetuses than in Tmprss6+/+ fetuses (p=.003). To determine if the increased hepcidin expression of Tmprss6-/- fetuses might affect iron homeostasis in their pregnant mothers, we measured iron parameters in Tmprss6+/− females gestating E17.5 litters that were enriched for either Tmprss6+/+ or Tmprss6-/- fetuses. No significant effects of fetal genotype on maternal iron parameters were observed. In summary, our results demonstrate that Tmprss6 regulates hepcidin expression in the fetal and neonatal periods in mice. However, Tmprss6 deficiency does not appear to be associated with systemic iron deficiency at these stages of development, and fetal Tmprss6 expression does not have a significant effect on maternal iron homeostasis in late gestation. These results may have implications for understanding the maintenance of iron homeostasis in early development, and may provide insight into the evolution of IRIDA as well as other disorders of iron homeostasis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals NCOA4 Expression in Hepatic Cells Is Upregulated Under Physiological and Pathophysiological Conditions Associated with Hypoxia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 431-431
Author(s):  
Xiuqi Li ◽  
Larisa Lozovatsky ◽  
Karin E. Finberg
Keyword(s):  
Hepatoma Cell ◽  
Fold Increase ◽  
Heme Iron ◽  
Hepatoma Cell Line ◽  
Hepatic Iron ◽  
Mrna Levels ◽  
Iron Stores ◽  
Pregnant Females ◽  
Non Heme Iron ◽  
Hep3b Cells

The ubiquitously expressed intracellular protein NCOA4 mediates the degradation of ferritin in vitro (Mancias et al., Nature 2014; Dowdle et al., Nat Cell Biol 2014) and its loss disrupts systemic iron balance in mice (Bellelli et al., Cell Rep 2016). While a mechanism for increased NCOA4 protein turnover under high iron conditions has been reported in transformed cell lines of non-hepatic origin (Mancias et al., Elife, 2015), factors that regulate NCOA4 mRNA levels have not yet been described. Here we investigate stimuli that induce NCOA4 mRNA expression in hepatoma cells as well as in liver, the major iron depot of the body. We found that treating the human hepatoma cell line, Hep3B, for 18 hrs with increasing concentrations of the iron chelator desferrioxamine (DFO; 25-100μM) resulted in significantly higher NCOA4 mRNA (ANOVA P&lt;.0001; 1.8 fold increase at the highest dose). Additionally, the murine hepatoma cell line, Hepa1-6, responded to 18 hrs of DFO treatment (25-100μM) with a dose-dependent rise in Ncoa4 mRNA levels (ANOVA P&lt;.0001; 2.7 fold increase at the highest dose). DFO treatment of Hep3B and Hepa1-6 cells also increased mRNA levels of the transferrin receptor, confirming induction of iron deficiency. Because DFO has also been shown to stabilize hypoxia inducible factor (HIF), we examined the effects of other chemical hypoxia mimetics on hepatoma cell lines. Hep3B cells treated for 18 hrs with CoCl2 (25-75 μM), which is known to enhance the stability of HIF1α, showed a 2-fold increase in NCOA4 mRNA (ANOVA; P&lt;.0001). Similarly, treatment of Hep3B cells with dimethyloxalylglycine (DMOG; 1mM), a competitive inhibitor of HIF prolyl-hydroxylases that promote HIF-α degradation, resulted in a 3-fold increase in NCOA4 mRNA at 12 hrs, which was further enhanced at 18 hrs. These results suggest that hepatoma cells in culture may respond to decreased iron availability and/or hypoxia by upregulating NCOA4 mRNA levels. We also investigated if Ncoa4 mRNA expression is upregulated in mouse livers under conditions associated with depletion of hepatic iron stores and/or hypoxia. C57BL/6N mice raised on a 45 p.p.m. iron diet were subjected to a large-volume phlebotomy (500μl; accompanied by intraperitoneal saline volume replacement) and fed an iron-deficient diet (2-6 p.p.m.) after bleeding. Seven days after phlebotomy, mice showed significantly lower blood hemoglobin levels (Student's T test P&lt;.0001) and hepatic non-heme iron concentrations (P&lt;.0001). However, the phlebotomized mice exhibited 1.8-fold higher hepatic Ncoa4 mRNA levels (P&lt;.01) compared to non-phlebotomized controls. Additionally, we examined if hepatic Ncoa4 expression changed during normal pregnancy, a state in which extra-hepatic iron demands are increased by both the expanding maternal blood volume and the growing fetus. Compared to non-pregnant females, C57BL/6N mice at day 18.5 of pregnancy showed significantly lower liver non-heme iron concentrations (P&lt;.01), while hepatic Ncoa4 mRNA levels were 3.5-fold higher (P&lt;.01) in pregnant females compared to non-pregnant controls. By mining a published murine gene expression dataset (GEO accession GDS5818), we found that hepatic Ncoa4 mRNA levels are relatively high in early life (embryonic day 18 and postnatal day 5) and decline by adulthood (postnatal day 56), suggesting a relatively greater hepatic requirement for NCOA4 function during periods of high growth. Collectively, these in vivo data show that Ncoa4 upregulation correlates with conditions in which mobilizing iron for systemic use takes precedence over building hepatic iron stores. In summary, we show for the first time that Ncoa4 mRNA rises significantly in physiological and pathophysiological states in which increased extra-hepatic iron demands induce a reduction in hepatic iron stores. Additionally, we show that Ncoa4 mRNA levels in cultured cells of hepatic origin rise in response to hypoxia mimetics. Because NCOA4 functions as a cargo receptor that traffics ferritin to the autolysosome, NCOA4 protein is expected to be consumed during the process of ferritinophagy. We suggest that upregulation of hepatic Ncoa4 mRNA in response to hypoxia may represent a physiological adaptation to replenish NCOA4 protein that is needed to support continued mobilization of iron from the liver during periods of increased systemic iron demands. Disclosures No relevant conflicts of interest to declare.

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