Iron metabolism is a critical factor in tumorigenesis and development. Although TP53 mutations are prevalent in glioblastoma (GBM), the mechanisms by which TP53 regulates iron metabolism remain elusive. We reveal an i...Iron metabolism is a critical factor in tumorigenesis and development. Although TP53 mutations are prevalent in glioblastoma (GBM), the mechanisms by which TP53 regulates iron metabolism remain elusive. We reveal an imbalance iron homeostasis in GBM via TCGA database analysis. TP53 mutations disrupted iron homeostasis in GBM, characterized by elevated total iron levels and reduced ferritin (FTH). The gain-of-function effect triggered by TP53 mutations upregulates itchy E3 ubiquitin-protein ligase (ITCH) protein expression in astrocytes, leading to FTH degradation and an increase in free iron levels. TP53-mut astrocytes were more tolerant to the high iron environment induced by exogenous ferric ammonium citrate (FAC), but the increase in intracellular free iron made them more sensitive to Erastin-induced ferroptosis. Interestingly, we found that Erastin combined with FAC treatment significantly increased ferroptosis. These findings provide new insights for drug development and therapeutic modalities for GBM patients with TP53 mutations from iron metabolism perspectives.展开更多
HOXA transcript at the distal tip(HOTTIP),a newly identified long noncoding RNA,has been shown to exhibit anti-inflammatory effects and inhibit oxygen-glucose deprivation-induced neuronal apoptosis.However,its role in...HOXA transcript at the distal tip(HOTTIP),a newly identified long noncoding RNA,has been shown to exhibit anti-inflammatory effects and inhibit oxygen-glucose deprivation-induced neuronal apoptosis.However,its role in Parkinson's disease(PD)remains unclear.1-Methyl-4-phenylpyridium(MPP+)and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)were used to establish PD models in SH-SY5 Y and BV2 cells and in C57 BL/6 male mice,respectively.In vitro,after HOTTIP knockdown by sh-HOTTIP transfection,HOTTIP and FOXO1 overexpression promoted SH-SY5 Y apoptosis,BV2 microglial activation,proinflammatory cytokine expression,and nuclear factor kappa-B and NACHT,LRR and PYD domains-containing protein 3 inflammasome activation.Overexpression of mi R-615-3 p inhibited MPP+-induced neuronal apoptosis and microglial inflammation and ameliorated HOTTIP-and FOXO1-mediated nerve injury and inflammation.In vivo,HOTTIP knockdown alleviated motor dysfunction in PD mice and reduced neuronal apoptosis and microglial activation in the substantia nigra.These findings suggest that inhibition of HOTTIP mitigates neuronal apoptosis and microglial activation in PD models by modulating mi R-615-3 p/FOXO1.This study was approved by the Ethics Review Committee of the Affiliated Hospital of Qingdao University,China(approval No.UDX-2018-042)in June 2018.展开更多
Background: We introduce a new catheter-based minimally invasive approach via frontal tuber for removing hypertensive intraventricular hemorrhage(IVH), and further compare its treatment efficacy with conventional exte...Background: We introduce a new catheter-based minimally invasive approach via frontal tuber for removing hypertensive intraventricular hemorrhage(IVH), and further compare its treatment efficacy with conventional external ventricular drainage (EVD).Methods: This study is prospective and randomized.Sixty cases of secondary intraventricular cast hemorrhage patients were randomly divided into two groups of 30 cases: modified ventricular puncture (MVP) group and control group.Preoperative Glasgow coma scale (GCS) and Graeb score were compared between the two groups.The postoperative manifestations of two groups were also analyzed and compared statistically, including evacuation rate of intraventricular hematoma in 24 h, the time with drainage tube, rebleeding, complicated by infection, shunt-dependent hydrocephalus and Glasgow outcome scale at 3 months.Results: 1.There was no significant difference in preoperative GCS score and the Graeb score between two groups (P ＞ 0.05).2.In the MVP group via frontal tuber approach, a substantial removal of intraventricular hematoma was achieved in all cases.The average evacuation rate of intraventricular hematoma reached 80.10 ± 10.16 ％, the average time of catheter drainage was 3.17 ± 0.87 days, the average GOS was 3.80 ± 0.92, no intracranial infection and secondary hemorrhage were observed following surgery in all cases, and shunt-dependent hydrocephalus occurred in 2 cases.In the control group, the hematoma evacuation rate was an average of 21.21 ± 7.81％, the time of drainage was an average of 7.63 ± 2.87 days, the GOS was an average of 3.20 ± 1.12, intracranial infection after surgery occurred in 5 cases, secondary hemorrhage was observed in 1 case, and shunt-dependent hydrocephalus occurred in 8 cases.Between the two groups there were significantly statistical difference in the hematoma evacuation rate, drainage duration, infection rate and GOS (all P ＜ 0.05).Conclusions: The new approach is safe, and can quickly remove the hematoma, and significantly shorten the time with a pipe.It can also reduce the occurrence of infection and hydrocephalus, and improve overall outcome of patients, but cannot reduce mortality.展开更多
基金supported by the National Natural Science Foundation of China(32171131,32371013,82071429,82471274,and 32371181)Shandong Province Natural Science Foundation(2021ZDSYS11,ZR2019ZD31,and ZR2022MC098)the Taishan Scholars Construction Project.
文摘Iron metabolism is a critical factor in tumorigenesis and development. Although TP53 mutations are prevalent in glioblastoma (GBM), the mechanisms by which TP53 regulates iron metabolism remain elusive. We reveal an imbalance iron homeostasis in GBM via TCGA database analysis. TP53 mutations disrupted iron homeostasis in GBM, characterized by elevated total iron levels and reduced ferritin (FTH). The gain-of-function effect triggered by TP53 mutations upregulates itchy E3 ubiquitin-protein ligase (ITCH) protein expression in astrocytes, leading to FTH degradation and an increase in free iron levels. TP53-mut astrocytes were more tolerant to the high iron environment induced by exogenous ferric ammonium citrate (FAC), but the increase in intracellular free iron made them more sensitive to Erastin-induced ferroptosis. Interestingly, we found that Erastin combined with FAC treatment significantly increased ferroptosis. These findings provide new insights for drug development and therapeutic modalities for GBM patients with TP53 mutations from iron metabolism perspectives.
文摘HOXA transcript at the distal tip(HOTTIP),a newly identified long noncoding RNA,has been shown to exhibit anti-inflammatory effects and inhibit oxygen-glucose deprivation-induced neuronal apoptosis.However,its role in Parkinson's disease(PD)remains unclear.1-Methyl-4-phenylpyridium(MPP+)and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)were used to establish PD models in SH-SY5 Y and BV2 cells and in C57 BL/6 male mice,respectively.In vitro,after HOTTIP knockdown by sh-HOTTIP transfection,HOTTIP and FOXO1 overexpression promoted SH-SY5 Y apoptosis,BV2 microglial activation,proinflammatory cytokine expression,and nuclear factor kappa-B and NACHT,LRR and PYD domains-containing protein 3 inflammasome activation.Overexpression of mi R-615-3 p inhibited MPP+-induced neuronal apoptosis and microglial inflammation and ameliorated HOTTIP-and FOXO1-mediated nerve injury and inflammation.In vivo,HOTTIP knockdown alleviated motor dysfunction in PD mice and reduced neuronal apoptosis and microglial activation in the substantia nigra.These findings suggest that inhibition of HOTTIP mitigates neuronal apoptosis and microglial activation in PD models by modulating mi R-615-3 p/FOXO1.This study was approved by the Ethics Review Committee of the Affiliated Hospital of Qingdao University,China(approval No.UDX-2018-042)in June 2018.
文摘Background: We introduce a new catheter-based minimally invasive approach via frontal tuber for removing hypertensive intraventricular hemorrhage(IVH), and further compare its treatment efficacy with conventional external ventricular drainage (EVD).Methods: This study is prospective and randomized.Sixty cases of secondary intraventricular cast hemorrhage patients were randomly divided into two groups of 30 cases: modified ventricular puncture (MVP) group and control group.Preoperative Glasgow coma scale (GCS) and Graeb score were compared between the two groups.The postoperative manifestations of two groups were also analyzed and compared statistically, including evacuation rate of intraventricular hematoma in 24 h, the time with drainage tube, rebleeding, complicated by infection, shunt-dependent hydrocephalus and Glasgow outcome scale at 3 months.Results: 1.There was no significant difference in preoperative GCS score and the Graeb score between two groups (P ＞ 0.05).2.In the MVP group via frontal tuber approach, a substantial removal of intraventricular hematoma was achieved in all cases.The average evacuation rate of intraventricular hematoma reached 80.10 ± 10.16 ％, the average time of catheter drainage was 3.17 ± 0.87 days, the average GOS was 3.80 ± 0.92, no intracranial infection and secondary hemorrhage were observed following surgery in all cases, and shunt-dependent hydrocephalus occurred in 2 cases.In the control group, the hematoma evacuation rate was an average of 21.21 ± 7.81％, the time of drainage was an average of 7.63 ± 2.87 days, the GOS was an average of 3.20 ± 1.12, intracranial infection after surgery occurred in 5 cases, secondary hemorrhage was observed in 1 case, and shunt-dependent hydrocephalus occurred in 8 cases.Between the two groups there were significantly statistical difference in the hematoma evacuation rate, drainage duration, infection rate and GOS (all P ＜ 0.05).Conclusions: The new approach is safe, and can quickly remove the hematoma, and significantly shorten the time with a pipe.It can also reduce the occurrence of infection and hydrocephalus, and improve overall outcome of patients, but cannot reduce mortality.
