| 1. |
- Han, W., et al.
(författare)
-
Dying transplanted neural stem cells mediate survival bystander effects in the injured brain
- 2023
-
Ingår i: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 14:3
-
Tidskriftsartikel (refereegranskat)abstract
- Neural stem and progenitor cell (NSPC) transplants provide neuroprotection in models of acute brain injury, but the underlying mechanisms are not fully understood. Here, we provide evidence that caspase-dependent apoptotic cell death of NSPCs is required for sending survival signals to the injured brain. The secretome of dying NSPCs contains heat-stable proteins, which protect neurons against glutamate-induced toxicity and trophic factor withdrawal in vitro, and from ischemic brain damage in vivo. Our findings support a new concept suggesting a bystander effect of apoptotic NSPCs, which actively promote neuronal survival through the release of a protective "farewell" secretome. Similar protective effects by the secretome of apoptotic NSPC were also confirmed in human neural progenitor cells and neural stem cells but not in mouse embryonic fibroblasts (MEF) or human dopaminergic neurons, suggesting that the observed effects are cell type specific and exist for neural progenitor/stem cells across species.
|
|
| 2. |
- Li, Tao, et al.
(författare)
-
AIF Overexpression Aggravates Oxidative Stress in Neonatal Male Mice After Hypoxia-Ischemia Injury
- 2022
-
Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 59:11, s. 6613-6631
-
Tidskriftsartikel (refereegranskat)abstract
- There are sex differences in the severity, mechanisms, and outcomes of neonatal hypoxia-ischemia (HI) brain injury, and apoptosis-inducing factor (AIF) may play a critical role in this discrepancy. Based on previous findings that AIF over-expression aggravates neonatal HI brain injury, we further investigated potential sex differences in the severity and molecular mechanisms underlying the injury using mice that overexpress AIF from homozygous transgenes. We found that the male sex significantly aggravated AIF-driven brain damage, as indicated by the injury volume in the gray matter (2.25 times greater in males) and by the lost volume of subcortical white matter (1.71 greater in males) after HI. As compared to females, male mice exhibited more severe brain injury, correlating with reduced antioxidant capacities, more pronounced protein carbonylation and nitration, and increased neuronal cell death. Under physiological conditions (without HI), the doublecortin-positive area in the dentate gyrus of females was 1.15 times larger than in males, indicating that AIF upregulation effectively promoted neurogenesis in females in the long term. We also found that AIF stimulated carbohydrate metabolism in young males. Altogether, these findings corroborate earlier studies and further demonstrate that AIF is involved in oxidative stress, which contributes to the sex-specific differences observed in neonatal HI brain injury.
|
|
| 3. |
- Li, Tao, et al.
(författare)
-
Overexpression of apoptosis inducing factor aggravates hypoxic-ischemic brain injury in neonatal mice
- 2020
-
Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Apoptosis inducing factor (AIF) has been shown to be a major contributor to neuron loss in the immature brain after hypoxia-ischemia (HI). Indeed, mice bearing a hypomorphic mutation causing reduced AIF expression are protected against neonatal HI. To further investigate the possible molecular mechanisms of this neuroprotection, we generated an AIF knock-in mouse by introduction of a latent transgene coding for flagged AIF protein into the Rosa26 locus, followed by its conditional activation by a ubiquitously expressed Cre recombinase. Such AIF transgenic mice overexpress the pro-apoptotic splice variant of AIF (AIF1) at both the mRNA (5.9 times higher) and protein level (2.4 times higher), but not the brain-specific AIF splice-isoform (AIF2). Excessive AIF did not have any apparent effects on the phenotype or physiological functions of the mice. However, brain injury (both gray and white matter) after neonatal HI was exacerbated in mice overexpressing AIF, coupled to enhanced translocation of mitochondrial AIF to the nucleus as well as enhanced caspase-3 activation in some brain regions, as indicated by immunohistochemistry. Altogether, these findings corroborate earlier studies demonstrating that AIF plays a causal role in neonatal HI brain injury.
|
|
| 4. |
- Rodriguez, Juan, 1983, et al.
(författare)
-
Inhibiting the interaction between apoptosis-inducing factor and cyclophilin A prevents brain injury in neonatal mice after hypoxia-ischemia
- 2020
-
Ingår i: Neuropharmacology. - : Elsevier BV. - 0028-3908 .- 1873-7064. ; 171
-
Tidskriftsartikel (refereegranskat)abstract
- © 2020 The Authors The interaction between apoptosis-inducing factor (AIF) and cyclophilin A (CypA) has been shown to contribute to caspase-independent apoptosis. Blocking the AIF/CypA interaction protects against glutamate-induced neuronal cell death in vitro, and the purpose of this study was to determine the in vivo effect of an AIF/CypA interaction blocking peptide (AIF(370-394)-TAT) on neonatal mouse brain injury after hypoxia-ischemia (HI). The pups were treated with AIF (370-394)-TAT peptide intranasally prior to HI. Brain injury was significantly reduced at 72 h after HI in the AIF(370-394)-TAT peptide treatment group compared to vehicle-only treatment for both the gray matter and the subcortical white matter, and the neuroprotection was more pronounced in males than in females. Neuronal cell death was evaluated in males at 8 h and 24 h post-HI, and it was decreased significantly in the CA1 region of the hippocampus and the nucleus habenularis region after AIF(370-394)-TAT treatment. Caspase-independent apoptosis was decreased in the cortex, striatum, and nucleus habenularis after AIF(370-394)-TAT treatment, but no significant change was found on caspase-dependent apoptosis as indicated by the number of active caspase-3-labeled cells. Further analysis showed that both AIF and CypA nuclear accumulation were decreased after treatment with the AIF(370-394)-TAT peptide. These results suggest that AIF(370-394)-TAT inhibited AIF/CypA translocation to the nucleus and reduced HI-induced caspase-independent apoptosis and brain injury in young male mice, suggesting that blocking AIF/CypA might be a potential therapeutic target for neonatal brain injury.
|
|
| 5. |
- Rodriguez, Juan, 1983, et al.
(författare)
-
Lack of the brain-specific isoform of apoptosis-inducing factor aggravates cerebral damage in a model of neonatal hypoxia-ischemia.
- 2018
-
Ingår i: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- Apoptosis-inducing factor (AIF) may contribute to neuronal cell death, and its influence is particularly prominent in the immature brain after hypoxia-ischemia (HI). A brain-specific AIF splice-isoform (AIF2) has recently been discovered, but has not yet been characterized at the genetic level. The aim of this study was to determine the functional and regulatory profile of AIF2 under physiological conditions and after HI in mice. We generated AIF2 knockout (KO) mice by removing the AIF2-specific exon and found that the relative expression of Aif1 mRNA increased in Aif2 KO mice and that this increase became even more pronounced as Aif2 KO mice aged compared to their wild-type (WT) littermates. Mitochondrial morphology and function, reproductive function, and behavior showed no differences between WT and Aif2 KO mice. However, lack of AIF2 enhanced brain injury in neonatal mice after HI compared to WT controls, and this effect was linked to increased oxidative stress but not to caspase-dependent or -independent apoptosis pathways. These results indicate that AIF2 deficiency exacerbates free radical production and HI-induced neonatal brain injury.
|
|
| 6. |
- Sun, Yanyan, et al.
(författare)
-
Dichloroacetate treatment improves mitochondrial metabolism and reduces brain injury in neonatal mice
- 2016
-
Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:22, s. 31708-31722
-
Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to evaluate the effect of dichloroacetate (DCA) treatment for brain injury in neonatal mice after hypoxia ischemia (HI) and the possible molecular mechanisms behind this effect. Postnatal day 9 male mouse pups were subjected to unilateral HI, DCA was injected intraperitoneally immediately after HI, and an additional two doses were administered at 24 h intervals. The pups were sacrificed 72 h after HI. Brain injury, as indicated by infarction volume, was reduced by 54.2% from 10.8 +/- 1.9 mm(3) in the vehicle-only control group to 5.0 +/- 1.0 mm(3) in the DCA-treated group at 72 h after HI (p = 0.008). DCA treatment also significantly reduced subcortical white matter injury as indicated by myelin basic protein staining (p = 0.018). Apoptotic cell death in the cortex, as indicated by counting the cells that were positive for apoptosis-inducing factor (p = 0.018) and active caspase-3 (p = 0.021), was significantly reduced after DCA treatment. The pyruvate dehydrogenase activity and the amount of acetyl-CoA in mitochondria was significantly higher after DCA treatment and HI (p = 0.039, p = 0.024). In conclusion, DCA treatment reduced neonatal mouse brain injury after HI, and this appears to be related to the elevated activation of pyruvate dehydrogenase and subsequent increase in mitochondrial metabolism as well as reduced apoptotic cell death.
|
|
| 7. |
- Sun, Yanyan, et al.
(författare)
-
Haploinsufficiency in the mitochondrial protein CHCHD4 reduces brain injury in a mouse model of neonatal hypoxia-ischemia
- 2017
-
Ingår i: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Mitochondria contribute to neonatal hypoxic-ischemic brain injury by releasing potentially toxic proteins into the cytosol. CHCHD4 is a mitochondrial intermembrane space protein that plays a major role in the import of intermembrane proteins and physically interacts with apoptosis-inducing factor (AIF). The purpose of this study was to investigate the impact of CHCHD4 haploinsufficiency on mitochondrial function and brain injury after cerebral hypoxia-ischemia (HI) in neonatal mice. CHCHD4(+/-) and wild-type littermate mouse pups were subjected to unilateral cerebral HI on postnatal day 9. CHCHD4 haploinsufficiency reduced insult-related AIF and superoxide dismutase 2 release from the mitochondria and reduced neuronal cell death. The total brain injury volume was reduced by 21.5% at 3 days and by 31.3% at 4 weeks after HI in CHCHD4(+/-) mice. However, CHCHD4 haploinsufficiency had no influence on mitochondrial biogenesis, fusion, or fission; neural stem cell proliferation; or neural progenitor cell differentiation. There were no significant changes in the expression or distribution of p53 protein or p53 pathway-related genes under physiological conditions or after HI. These results suggest that CHCHD4 haploinsufficiency afforded persistent neuroprotection related to reduced release of mitochondrial intermembrane space proteins. The CHCHD4-dependent import pathway might thus be a potential therapeutic target for preventing or treating neonatal brain injury.
|
|
| 8. |
- Wang, Yafeng, 1985, et al.
(författare)
-
Autophagy Inhibition Reduces Irradiation-Induced Subcortical White Matter Injury Not by Reducing Inflammation, but by Increasing Mitochondrial Fusion and Inhibiting Mitochondrial Fission
- 2022
-
Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 59:2, s. 1199-1213
-
Tidskriftsartikel (refereegranskat)abstract
- Radiotherapy is an effective tool in the treatment of malignant brain tumors, but irradiation-induced late-onset toxicity remains a major problem. The purpose of this study was to investigate if genetic inhibition of autophagy has an impact on subcortical white matter development in the juvenile mouse brain after irradiation. Ten-day-old selective neural Atg7 knockout (KO) mice and wild-type (WT) littermates were subjected to a single 6-Gy dose of whole-brain irradiation and evaluated at 5 days after irradiation. Neural Atg7 deficiency partially prevented myelin disruption compared to the WT mice after irradiation, as indicated by myelin basic protein staining. Irradiation induced oligodendrocyte progenitor cell loss in the subcortical white matter, and Atg7 deficiency partly prevented this. There was no significant change between the KO and WT mice in the number of microglia and astrocytes in the subcortical white matter after irradiation. Transcriptome analysis showed that the GO mitochondrial gene expression pathway was significantly enriched in the differentially expressed genes between the KO and WT group after irradiation. Compared with WT mice, expression of the mitochondrial fusion protein OPA1 and phosphorylation of the mitochondrial fission protein DRP1 (P-DRP1) were dramatically decreased in KO mice under physiological conditions. The protein levels of OPA1and P-DRP1 showed no differences in WT mice between the non-irradiated group and the irradiated group but had remarkably increased levels in the KO mice after irradiation. These results indicate that inhibition of autophagy reduces irradiation-induced subcortical white matter injury not by reducing inflammation, but by increasing mitochondrial fusion and inhibiting mitochondrial fission.
|
|
| 9. |
- Wang, Y. F., et al.
(författare)
-
Cerebellar irradiation does not cause hyperactivity, fear, and anxiety-related disorders in the juvenile rat brain
- 2022
-
Ingår i: European Radiology Experimental. - : Springer Science and Business Media LLC. - 2509-9280. ; 6:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background The cerebellum is involved in hyperactivity, fear, and anxiety disorders that could be induced by whole-brain irradiation (WBI). However, whether cerebellar irradiation alone (CIA) could induce these disorders is unknown. We investigated the effect of CIA in an animal model. Methods Eleven-day-old rat pups underwent a single 3-Gy dose of either WBI (n = 28) or CIA (n = 20), while 34 rat pups were sham-irradiated (controls). Cell death was evaluated in the subgranular zone of the hippocampus by counting pyknotic cells after haematoxylin/eosin staining at 6 h after irradiation for 10, 8, and 9 pups, respectively. Behavioural changes were evaluated via open-field test at 6 weeks for 18, 12, and 25 pups, respectively. Unpaired two-tailed t-test and one-way and two-way repeated ANOVA were used. Results Massive cell death in cerebellar external granular layer was detected at 6 h after CIA (1,419 +/- 211 mm, mean +/- S.E.M. versus controls (68 +/- 12 mm) (p < 0.001)), while no significant difference between CIA (1,419 +/- 211 mm) versus WBI (1,433 +/- 107 mm) (p = 0.955) was found. At open-field behavioural test, running distance, activity, wall distance, middle zone visit times, and duration were higher for WBI versus controls (p < 0.010), but no difference between CIA and controls was found (p > 0.05). Conclusions Although the cerebellum is involved in hyperactivity, fear, and anxiety disorders, CIA did not induce these disorders, indicating that WBI-induced cerebellar injury does not directly cause these behavioural abnormalities after WBI. Thus, targeting the cerebellum alone may not be enough to rescue or reduce these behavioural abnormalities after WBI.
|
|
| 10. |
- Wang, Yafeng, 1985, et al.
(författare)
-
Inhibition of autophagy prevents irradiation-induced neural stem and progenitor cell death in the juvenile mouse brain
- 2017
-
Ingår i: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 8:3
-
Tidskriftsartikel (refereegranskat)abstract
- Radiotherapy is an effective tool in the treatment of malignant brain tumors. However, damage to brain stem and progenitor cells constitutes a major problem and is associated with long-term side effects. Autophagy has been shown to be involved in cell death, and the purpose of this study was to evaluate the effect of autophagy inhibition on neural stem and progenitor cell death in the juvenile brain. Ten-day-old selective Atg7 knockout (KO) mice and wild-type (WT) littermates were subjected to a single 6Gy dose of whole-brain irradiation. Cell death and proliferation as well as microglia activation and inflammation were evaluated in the dentate gyrus of the hippocampus and in the cerebellum at 6 h after irradiation. We found that cell death was reduced in Atg7 KO compared with WT mice at 6 h after irradiation. The number of activated microglia increased significantly in both the dentate gyrus and the cerebellum of WT mice after irradiation, but the increase was lower in the Atg7 KO mice. The levels of proinflammatory cytokines and chemokines decreased, especially in the cerebellum, in the Atg7 KO group. These results suggest that autophagymight be a potential target for preventing radiotherapy-induced neural stem and progenitor cell death and its associated long-term side effects.
|
|
