The mechanisms by which breviscapine (Bre) inhibits the lipid preoxidation in rat brain mitochondria were investigated. The mitochondrial lipid peroxidation of rat brain induced by oxygen free radical was measured by ...The mechanisms by which breviscapine (Bre) inhibits the lipid preoxidation in rat brain mitochondria were investigated. The mitochondrial lipid peroxidation of rat brain induced by oxygen free radical was measured by thiobarbituric acid spectrophotometry. The chelating activities of Bre for Fe 2+ were tested by differential spectrum. Superoxide anion (O 2)from xanthine xanthine oxidase (Xan XO) system and hydroxyl radical (·OH) from FeSO 4 H 2O 2 system were determined with spectrophotometry. It was found that Bre could effectively inhibit the lipid peroxidation of brain mitochondria induced by free radicals driven from Xan XO and FeSO 4 H 2O 2 system. The IC 50 of Bre were 93 01 μmol·L -1 for Xan XO system and 62 18 μmol·L -1 for FeSO 4 H 2O 2 system. Bre also scavenged O 2 and ·OH produced by Xan XO and FeSO 4 H 2O 2 systems. The IC 50 of Bre were 32 63 μmol·L -1 for O - 2 and 20 22 μmol·L -1 for ·OH. Furthermore, the chelating Fe 2+ activity of Bre was shown. It may be concluded that Bre inhibited lipid peroxidation at different stages of the reaction of oxygen free redial with the mitochondria membrane: (1) the formation of ·OH; (2) the initiation of the lipid peroxidation, by chelating Fe 2+ and scavenging O 2 as well as ·OH. The scavenging oxygen free radicals and chelating iron are the mechanisms of inhibitory effect of Bre on lipid peroxidation.展开更多
Telomerase is an enzyme that maintains telomeres in dividing cells using a template on its inherent RNA component.Additionally,the protein part TERT（Telomerase Reverse Transcriptase） has various non-canonical functi...Telomerase is an enzyme that maintains telomeres in dividing cells using a template on its inherent RNA component.Additionally,the protein part TERT（Telomerase Reverse Transcriptase） has various non-canonical functions.For example,it can localize to mitochondria under increased stress and protect cells in vitro from oxidative stress,DNA damage and apoptosis.Recently it has been demonstrated that TERT protein persists in adult neurons in the brain and data emerge suggesting that it might have a protective function in these post-mitotic cells as well.We have recently published that TERT protein accumulated in mitochondria from brain tissue of mice that have undergone short-term dietary restriction（DR） and rapamycin treatment.This localization correlated to lower levels of oxidative stress in these brain mitochondria.Since rapamycin treatment decreases mTOR signaling which is also thought to play an important role for the beneficial effects of DR,we conclude that the mTOR pathway might be involved in the TERT localization and its effects in brain mitochondria in vivo.These data are in line with previous findings from our group about increased mitochondrial localization of TERT in Alzheimer＇s disease（AD） brains and a protective function of TERT protein in neurons in vitro against pathological tau.展开更多
Traumatic brain injury （TBI） is an acquired injury to the brain that occurs with sudden trauma that can range from mild （concussive） to severe. TBI is considered a leading cause of death in children and young adul...Traumatic brain injury （TBI） is an acquired injury to the brain that occurs with sudden trauma that can range from mild （concussive） to severe. TBI is considered a leading cause of death in children and young adults, with the Centers for Disease Control and Prevention estimating that approximately 1.7 million cases of TBI occur in the United States annually （Faul et al., 2010）. Further, since the begin- ning of the global war on terrorism, the Department of Defense has reported over 344,000 U.S. Service Members have been diagnosed with traumatic brain injury from penetrating injuries to mild forms of TBI. TBI, caused by a sudden impact, penetration, or rapid move- ment of the brain, interrupts the normal functioning of the brain. While the intracranial location and severity of injury contribute to the extent of functional deficits.展开更多
Polydatin is thought to protect mitochondria in different cell types in various diseases.Mitochondrial dysfunction is a major contributing factor in secondary brain injury resulting from traumatic brain injury.To inve...Polydatin is thought to protect mitochondria in different cell types in various diseases.Mitochondrial dysfunction is a major contributing factor in secondary brain injury resulting from traumatic brain injury.To investigate the protective effect of polydatin after traumatic brain injury,a rat brain injury model of lateral fluid percussion was established to mimic traumatic brain injury insults.Rat models were intraperitoneally injected with polydatin(30 mg/kg)or the SIRT1 activator SRT1720(20 mg/kg,as a positive control to polydatin).At 6 hours post-traumatic brain injury insults,western blot assay was used to detect the expression of SIRT1,endoplasmic reticulum stress related proteins and p38 phosphorylation in cerebral cortex on the injured side.Flow cytometry was used to analyze neuronal mitochondrial superoxide,mitochondrial membrane potential and mitochondrial permeability transition pore opened.Ultrastructural damage in neuronal mitochondria was measured by transmission electron microscopy.Our results showed that after treatment with polydatin,release of reactive oxygen species in neuronal mitochondria was markedly reduced;swelling of mitochondria was alleviated;mitochondrial membrane potential was maintained;mitochondrial permeability transition pore opened.Also endoplasmic reticulum stress related proteins were inhibited,including the activation of p-PERK,spliced XBP-1 and cleaved ATF6.SIRT1 expression and activity were increased;p38 phosphorylation and cleaved caspase-9/3 activation were inhibited.Neurological scores of treated rats were increased and the mortality was reduced compared with the rats only subjected to traumatic brain injury.These results indicated that polydatin protectrd rats from the consequences of traumatic brain injury and exerted a protective effect on neuronal mitochondria.The mechanisms may be linked to increased SIRT1 expression and activity,which inhibits the p38 phosphorylation-mediated mitochondrial apoptotic pathway.This study was approved by the Animal Care and Use Committee of the Southern Medical University,China(approval number:L2016113)on January 1,2016.展开更多
The selective degradation of damaged or excessive mitochondria by autophagy is termed mitophagy. Mitophagy is crucial for mitochondrial quality control and has been implicated in several neurodegenerative disorders as...The selective degradation of damaged or excessive mitochondria by autophagy is termed mitophagy. Mitophagy is crucial for mitochondrial quality control and has been implicated in several neurodegenerative disorders as well as in ischemic brain injury. Emerging evidence suggested that the role of mitophagy in cerebral ischemia may depend on different pathological processes. In particular, a neuroprotective role of mitophagy has been proposed, and the regulation of mitophagy seems to be important in cell survival. For these reasons, extensive investigations aimed to profile the mitophagy process and its underlying molecular mechanisms have been executed in recent years. In this review, we summarize the current knowledge regarding the mitophagy process and its role in cerebral ischemia, and focus on the pathological events and molecules that regulate mitophagy in ischemic brain injury.展开更多
With the rapid development of electronic technologies, anxiety regarding the potential health hazards induced by microwave radiation(MW) has been growing in recent years. The brain is one of the most sensitive target ...With the rapid development of electronic technologies, anxiety regarding the potential health hazards induced by microwave radiation(MW) has been growing in recent years. The brain is one of the most sensitive target organs for microwave radiation, where mitochondrial injury occurs earlier and more severely than in other organs. Energy metabolism disorders do play an important role during the process of microwave radiation-induced brain damage. In this paper, we will review the biological effects of microwave radiation, the features of brain energy supply and consumption and the effects of microwave radiation on mitochondrial energy metabolism and potential related mechanisms.展开更多
Mitochondrial dysfunction is the key pathogenic mechanism of cerebral injury induced by high-altitude hypoxia.Some Chinese herbal monomers may exert anti-hypoxic effects through enhancing the efficiency of oxidative p...Mitochondrial dysfunction is the key pathogenic mechanism of cerebral injury induced by high-altitude hypoxia.Some Chinese herbal monomers may exert anti-hypoxic effects through enhancing the efficiency of oxidative phosphorylation,in this study,effects of 10 kinds of Chinese herbal monomers on mitochondrial respiration and membrane potential of cerebral mitochondria isolated from hypoxia-exposed rats in vitro were investigated to screen anti-hypoxic drugs.Rats were exposed to a low-pressure environment of 405.35 mm Hg(54.04 kPa)for 3 days to establish high-altitude hypoxic models.Cerebral mitochondria were isolated and treated with different concentrations of Chinese herbal monomers(sinomenine,silymarin,glycyrrhizic acid,baicalin,quercetin,ginkgolide B,saffron,pipedne,ginsenoside Rgl and oxymatrine)for 5 minutes in vitro.Mitochondrial oxygen consumption and membrane potential were measured using a Clark oxygen electrode and the rhodamine 123 fluorescence analysis method,respectively.Hypoxic exposure significantly decreased the state 3 respiratory rate,respiratory control rate and mitochondrial membrane potential,and significantly increased the state 4 respiratory rate.Treatment with saffron ginsenoside Rgl and oxymatrine increased the respiratory control rate in cerebral mitochondria isolated from hypoxia-exposed rats in dose-dependent manners in vitro,while ginsenoside Rgl,piperine and oxymatrine significantly increased the mitochondrial membrane potential in cerebral mitochondria from hypoxia-exposed rats.The Chinese herbal monomers saffron,ginsenoside Rgl piperine and oxymatrine could thus improve cerebral mitochondrial disorders in oxidative phosphorylation induced by hypobaric hypoxia exposure in vitro.展开更多
Apoptosis after traumatic brain injury has been shown to be a major factor influencing prognosis and outcome. Endoplasmic reticulum stress may be involved in mitochondrial mediated neuronal apoptosis. Therefore, endop...Apoptosis after traumatic brain injury has been shown to be a major factor influencing prognosis and outcome. Endoplasmic reticulum stress may be involved in mitochondrial mediated neuronal apoptosis. Therefore, endoplasmic reticulum stress has become an important mechanism of secondary injury after traumatic brain injury. In this study, a rat model of traumatic brain injury was established by lateral fluid percussion injury. Fluorescence assays were used to measure reactive oxygen species content in the cerebral cortex. Western blot assays were used to determine expression of endoplasmic reticulum stress-related proteins. Hematoxylin-eosin staining was used to detect pathological changes in the cerebral cortex. Transmission electron microscopy was used to measure ultrastructural changes in the endoplasmic reticulum and mitochondria. Our results showed activation of the endoplasmic reticulum stress-related unfolded protein response. Meanwhile, both the endoplasmic reticulum stress response and mitochondrial apoptotic pathway were activated at different stages post-traumatic brain injury. Furthermore, pretreatment with the endoplasmic reticulum stress inhibitor, salubrinal（1 mg/kg）, by intraperitoneal injection 30 minutes before injury significantly inhibited the endoplasmic reticulum stress response and reduced apoptosis. Moreover, salubrinal promoted recovery of mitochondrial function and inhibited activation of the mitochondrial apoptotic pathway post-traumatic brain injury. These results suggest that endoplasmic reticulum stress might be a key factor for secondary brain injury post-traumatic brain injury.展开更多
Hypobaric hypoxia can cause severe brain damage and mitochondrial dysfunction, and is involved in hypoxic brain injury. However, little is currently known about the mechanisms responsible for mi- tochondrial dysfuncti...Hypobaric hypoxia can cause severe brain damage and mitochondrial dysfunction, and is involved in hypoxic brain injury. However, little is currently known about the mechanisms responsible for mi- tochondrial dysfunction in hypobaric hypoxic brain damage. In this study, a rat model of hypobaric hypoxic brain injury was established to investigate the molecular mechanisms associated with mi- tochondrial dysfunction. As revealed by two-dimensional electrophoresis analysis, 16, 21, and 36 differential protein spots in cerebral mitochondria were observed at 6, 12, and 24 hours post-hypobaric hypoxia, respectively. Furthermore, ten protein spots selected from each hypobaric hypoxia subgroup were similarly regulated and were identified by mass spectrometry. These de- tected proteins included dihydropyrimidinase-related protein 2, creatine kinase B-type, is- ovaleryI-CoA dehydrogenase, elongation factor Ts, ATP synthase beta-subunit, 3-mercaptopyruvate sulfurtransferase, electron transfer flavoprotein alpha-subunit, Chain A of 2-enoyI-CoA hydratase, NADH dehydrogenase iron-sulfur protein 8 and tropomyosin beta chain. These ten proteins are all involved in the electron transport chain and the function of ATP synthase. Our findings indicate that hypobaric hypoxia can induce the differential expression of several cerebral mitochondrial proteins, which are involved in the regulation of mitochondrial energy production.展开更多
Selective brain hypothermia is considered an effective treatment for neuronal injury after stroke,and avoids the complications of general hypothermia.However,the mechanisms by which selective brain hypothermia affects...Selective brain hypothermia is considered an effective treatment for neuronal injury after stroke,and avoids the complications of general hypothermia.However,the mechanisms by which selective brain hypothermia affects mitochondrial fission remain unknown.In this study,we investigated the effect of selective brain hypothermia on the expression of fission 1 (Fis1) protein,a key factor in the mitochondrial fission system,during focal cerebral ischemia/reperfusion injury.Sprague-Dawley rats were divided into four groups.In the sham group,the carotid arteries were exposed only.In the other three groups,middle cerebral artery occlusion was performed using the intraluminal filament technique.After 2 hours of occlusion,the filament was slowly removed to allow blood reperfusion in the ischemia/reperfusion group.Saline,at 4℃ and 37℃,were perfused through the carotid artery in the hypothermia and normothermia groups,respectively,followed by restoration of blood flow.Neurological function was assessed with the Zea Longa 5-point scoring method.Cerebral infarct volume was assessed by 2,3,5-triphenyltetrazolium chloride staining,and apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining.Fis1 and cytosolic cytochrome c levels were assessed by western blot assay.Fis1 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction.Mitochondrial ultrastructure was evaluated by transmission electron microscopy.Compared with the sham group,apoptosis,Fis1 protein and mRNA expression and cytosolic cytochrome c levels in the cortical ischemic penumbra and cerebral infarct volume were increased after reperfusion in the other three groups.These changes caused by cerebral ischemia/reperfusion were inhibited in the hypothermia group compared with the normothermia group.These findings show that selective brain hypothermia inhibits Fis1 expression and reduces apoptosis,thereby ameliorating focal cerebral ischemia/reperfusion injury in rats.Experiments were authorized by the Ethics Committee of Qingdao Municipal Hospital of China (approval No.2019008).展开更多
Apolipoprotein E plays a crucial role in inhibiting chronic neurodegenerative processes. Howev-er, its impact on neurological function following diffuse brain injury is still unclear. This study was designed to evalua...Apolipoprotein E plays a crucial role in inhibiting chronic neurodegenerative processes. Howev-er, its impact on neurological function following diffuse brain injury is still unclear. This study was designed to evaluate the therapeutic effects and mechanisms of action of apolipoprotein E mimetic peptide on diffuse brain injury. Apolipoprotein E mimetic peptide was administered into the caudal vein of rats with diffuse brain injury before and after injury. We found that apo-lipoprotein E mimetic peptide signiifcantly decreased the number of apoptotic neurons, reduced extracellular signal-regulated kinase1/2 phosphorylation, down-regulated Bax and cytochrome c expression, decreased malondialdehyde content, and increased superoxide dismutase activity in a dose-dependent manner. These experimental ifndings demonstrate that apolipoprotein E mimetic peptide improves learning and memory function and protects against diffuse brain injury-induced apoptosis by inhibiting the extracellular signal-regulated kinase1/2-Bax mito-chondrial apoptotic pathway.展开更多
文摘The mechanisms by which breviscapine (Bre) inhibits the lipid preoxidation in rat brain mitochondria were investigated. The mitochondrial lipid peroxidation of rat brain induced by oxygen free radical was measured by thiobarbituric acid spectrophotometry. The chelating activities of Bre for Fe 2+ were tested by differential spectrum. Superoxide anion (O 2)from xanthine xanthine oxidase (Xan XO) system and hydroxyl radical (·OH) from FeSO 4 H 2O 2 system were determined with spectrophotometry. It was found that Bre could effectively inhibit the lipid peroxidation of brain mitochondria induced by free radicals driven from Xan XO and FeSO 4 H 2O 2 system. The IC 50 of Bre were 93 01 μmol·L -1 for Xan XO system and 62 18 μmol·L -1 for FeSO 4 H 2O 2 system. Bre also scavenged O 2 and ·OH produced by Xan XO and FeSO 4 H 2O 2 systems. The IC 50 of Bre were 32 63 μmol·L -1 for O - 2 and 20 22 μmol·L -1 for ·OH. Furthermore, the chelating Fe 2+ activity of Bre was shown. It may be concluded that Bre inhibited lipid peroxidation at different stages of the reaction of oxygen free redial with the mitochondria membrane: (1) the formation of ·OH; (2) the initiation of the lipid peroxidation, by chelating Fe 2+ and scavenging O 2 as well as ·OH. The scavenging oxygen free radicals and chelating iron are the mechanisms of inhibitory effect of Bre on lipid peroxidation.
文摘Telomerase is an enzyme that maintains telomeres in dividing cells using a template on its inherent RNA component.Additionally,the protein part TERT（Telomerase Reverse Transcriptase） has various non-canonical functions.For example,it can localize to mitochondria under increased stress and protect cells in vitro from oxidative stress,DNA damage and apoptosis.Recently it has been demonstrated that TERT protein persists in adult neurons in the brain and data emerge suggesting that it might have a protective function in these post-mitotic cells as well.We have recently published that TERT protein accumulated in mitochondria from brain tissue of mice that have undergone short-term dietary restriction（DR） and rapamycin treatment.This localization correlated to lower levels of oxidative stress in these brain mitochondria.Since rapamycin treatment decreases mTOR signaling which is also thought to play an important role for the beneficial effects of DR,we conclude that the mTOR pathway might be involved in the TERT localization and its effects in brain mitochondria in vivo.These data are in line with previous findings from our group about increased mitochondrial localization of TERT in Alzheimer＇s disease（AD） brains and a protective function of TERT protein in neurons in vitro against pathological tau.
文摘Traumatic brain injury （TBI） is an acquired injury to the brain that occurs with sudden trauma that can range from mild （concussive） to severe. TBI is considered a leading cause of death in children and young adults, with the Centers for Disease Control and Prevention estimating that approximately 1.7 million cases of TBI occur in the United States annually （Faul et al., 2010）. Further, since the begin- ning of the global war on terrorism, the Department of Defense has reported over 344,000 U.S. Service Members have been diagnosed with traumatic brain injury from penetrating injuries to mild forms of TBI. TBI, caused by a sudden impact, penetration, or rapid move- ment of the brain, interrupts the normal functioning of the brain. While the intracranial location and severity of injury contribute to the extent of functional deficits.
基金supported by the National Natural Science Foundation of China,No.81501690(to ZTG)the Scientific Research Staring Foundation for Talent Introduction for Southern Medical University(to MM)
文摘Polydatin is thought to protect mitochondria in different cell types in various diseases.Mitochondrial dysfunction is a major contributing factor in secondary brain injury resulting from traumatic brain injury.To investigate the protective effect of polydatin after traumatic brain injury,a rat brain injury model of lateral fluid percussion was established to mimic traumatic brain injury insults.Rat models were intraperitoneally injected with polydatin(30 mg/kg)or the SIRT1 activator SRT1720(20 mg/kg,as a positive control to polydatin).At 6 hours post-traumatic brain injury insults,western blot assay was used to detect the expression of SIRT1,endoplasmic reticulum stress related proteins and p38 phosphorylation in cerebral cortex on the injured side.Flow cytometry was used to analyze neuronal mitochondrial superoxide,mitochondrial membrane potential and mitochondrial permeability transition pore opened.Ultrastructural damage in neuronal mitochondria was measured by transmission electron microscopy.Our results showed that after treatment with polydatin,release of reactive oxygen species in neuronal mitochondria was markedly reduced;swelling of mitochondria was alleviated;mitochondrial membrane potential was maintained;mitochondrial permeability transition pore opened.Also endoplasmic reticulum stress related proteins were inhibited,including the activation of p-PERK,spliced XBP-1 and cleaved ATF6.SIRT1 expression and activity were increased;p38 phosphorylation and cleaved caspase-9/3 activation were inhibited.Neurological scores of treated rats were increased and the mortality was reduced compared with the rats only subjected to traumatic brain injury.These results indicated that polydatin protectrd rats from the consequences of traumatic brain injury and exerted a protective effect on neuronal mitochondria.The mechanisms may be linked to increased SIRT1 expression and activity,which inhibits the p38 phosphorylation-mediated mitochondrial apoptotic pathway.This study was approved by the Animal Care and Use Committee of the Southern Medical University,China(approval number:L2016113)on January 1,2016.
基金supported by the National Natural Science Foundation of China (81373393 and 81273506)the Zhejiang Provincial Natural Science Foundation (LR15H310001)+1 种基金the Program for Zhejiang Provincial Leading Team of S&T Innovation Team (2011R50014)the Fundamental Research Funds for the Central Universities,China (2015FZA7018)
文摘The selective degradation of damaged or excessive mitochondria by autophagy is termed mitophagy. Mitophagy is crucial for mitochondrial quality control and has been implicated in several neurodegenerative disorders as well as in ischemic brain injury. Emerging evidence suggested that the role of mitophagy in cerebral ischemia may depend on different pathological processes. In particular, a neuroprotective role of mitophagy has been proposed, and the regulation of mitophagy seems to be important in cell survival. For these reasons, extensive investigations aimed to profile the mitophagy process and its underlying molecular mechanisms have been executed in recent years. In this review, we summarize the current knowledge regarding the mitophagy process and its role in cerebral ischemia, and focus on the pathological events and molecules that regulate mitophagy in ischemic brain injury.
文摘With the rapid development of electronic technologies, anxiety regarding the potential health hazards induced by microwave radiation(MW) has been growing in recent years. The brain is one of the most sensitive target organs for microwave radiation, where mitochondrial injury occurs earlier and more severely than in other organs. Energy metabolism disorders do play an important role during the process of microwave radiation-induced brain damage. In this paper, we will review the biological effects of microwave radiation, the features of brain energy supply and consumption and the effects of microwave radiation on mitochondrial energy metabolism and potential related mechanisms.
基金supported by the Natural Science Foundation of China,No.81171875
文摘Mitochondrial dysfunction is the key pathogenic mechanism of cerebral injury induced by high-altitude hypoxia.Some Chinese herbal monomers may exert anti-hypoxic effects through enhancing the efficiency of oxidative phosphorylation,in this study,effects of 10 kinds of Chinese herbal monomers on mitochondrial respiration and membrane potential of cerebral mitochondria isolated from hypoxia-exposed rats in vitro were investigated to screen anti-hypoxic drugs.Rats were exposed to a low-pressure environment of 405.35 mm Hg(54.04 kPa)for 3 days to establish high-altitude hypoxic models.Cerebral mitochondria were isolated and treated with different concentrations of Chinese herbal monomers(sinomenine,silymarin,glycyrrhizic acid,baicalin,quercetin,ginkgolide B,saffron,pipedne,ginsenoside Rgl and oxymatrine)for 5 minutes in vitro.Mitochondrial oxygen consumption and membrane potential were measured using a Clark oxygen electrode and the rhodamine 123 fluorescence analysis method,respectively.Hypoxic exposure significantly decreased the state 3 respiratory rate,respiratory control rate and mitochondrial membrane potential,and significantly increased the state 4 respiratory rate.Treatment with saffron ginsenoside Rgl and oxymatrine increased the respiratory control rate in cerebral mitochondria isolated from hypoxia-exposed rats in dose-dependent manners in vitro,while ginsenoside Rgl,piperine and oxymatrine significantly increased the mitochondrial membrane potential in cerebral mitochondria from hypoxia-exposed rats.The Chinese herbal monomers saffron,ginsenoside Rgl piperine and oxymatrine could thus improve cerebral mitochondrial disorders in oxidative phosphorylation induced by hypobaric hypoxia exposure in vitro.
文摘Apoptosis after traumatic brain injury has been shown to be a major factor influencing prognosis and outcome. Endoplasmic reticulum stress may be involved in mitochondrial mediated neuronal apoptosis. Therefore, endoplasmic reticulum stress has become an important mechanism of secondary injury after traumatic brain injury. In this study, a rat model of traumatic brain injury was established by lateral fluid percussion injury. Fluorescence assays were used to measure reactive oxygen species content in the cerebral cortex. Western blot assays were used to determine expression of endoplasmic reticulum stress-related proteins. Hematoxylin-eosin staining was used to detect pathological changes in the cerebral cortex. Transmission electron microscopy was used to measure ultrastructural changes in the endoplasmic reticulum and mitochondria. Our results showed activation of the endoplasmic reticulum stress-related unfolded protein response. Meanwhile, both the endoplasmic reticulum stress response and mitochondrial apoptotic pathway were activated at different stages post-traumatic brain injury. Furthermore, pretreatment with the endoplasmic reticulum stress inhibitor, salubrinal（1 mg/kg）, by intraperitoneal injection 30 minutes before injury significantly inhibited the endoplasmic reticulum stress response and reduced apoptosis. Moreover, salubrinal promoted recovery of mitochondrial function and inhibited activation of the mitochondrial apoptotic pathway post-traumatic brain injury. These results suggest that endoplasmic reticulum stress might be a key factor for secondary brain injury post-traumatic brain injury.
基金supported by the National Natural Science Foundation of China,No.81073152the Key Science Foundation of Tianjin in China,No.10JCZDJC21100+1 种基金the Natural Science Foundation of Tianjin in China,No.10JCYBJC14700,No.13JCQNJC13200the Science Foundation of Tianjin Key Laboratory in China,No.WHTD 201303-2
文摘Hypobaric hypoxia can cause severe brain damage and mitochondrial dysfunction, and is involved in hypoxic brain injury. However, little is currently known about the mechanisms responsible for mi- tochondrial dysfunction in hypobaric hypoxic brain damage. In this study, a rat model of hypobaric hypoxic brain injury was established to investigate the molecular mechanisms associated with mi- tochondrial dysfunction. As revealed by two-dimensional electrophoresis analysis, 16, 21, and 36 differential protein spots in cerebral mitochondria were observed at 6, 12, and 24 hours post-hypobaric hypoxia, respectively. Furthermore, ten protein spots selected from each hypobaric hypoxia subgroup were similarly regulated and were identified by mass spectrometry. These de- tected proteins included dihydropyrimidinase-related protein 2, creatine kinase B-type, is- ovaleryI-CoA dehydrogenase, elongation factor Ts, ATP synthase beta-subunit, 3-mercaptopyruvate sulfurtransferase, electron transfer flavoprotein alpha-subunit, Chain A of 2-enoyI-CoA hydratase, NADH dehydrogenase iron-sulfur protein 8 and tropomyosin beta chain. These ten proteins are all involved in the electron transport chain and the function of ATP synthase. Our findings indicate that hypobaric hypoxia can induce the differential expression of several cerebral mitochondrial proteins, which are involved in the regulation of mitochondrial energy production.
基金supported by the Natural Science Foundation of Shandong Province of China,No.ZR2015HM023(to MSW)the Science and Technology Plan Project of Qingdao City of China,No.19-6-1-50-nsh(to MSW)
文摘Selective brain hypothermia is considered an effective treatment for neuronal injury after stroke,and avoids the complications of general hypothermia.However,the mechanisms by which selective brain hypothermia affects mitochondrial fission remain unknown.In this study,we investigated the effect of selective brain hypothermia on the expression of fission 1 (Fis1) protein,a key factor in the mitochondrial fission system,during focal cerebral ischemia/reperfusion injury.Sprague-Dawley rats were divided into four groups.In the sham group,the carotid arteries were exposed only.In the other three groups,middle cerebral artery occlusion was performed using the intraluminal filament technique.After 2 hours of occlusion,the filament was slowly removed to allow blood reperfusion in the ischemia/reperfusion group.Saline,at 4℃ and 37℃,were perfused through the carotid artery in the hypothermia and normothermia groups,respectively,followed by restoration of blood flow.Neurological function was assessed with the Zea Longa 5-point scoring method.Cerebral infarct volume was assessed by 2,3,5-triphenyltetrazolium chloride staining,and apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining.Fis1 and cytosolic cytochrome c levels were assessed by western blot assay.Fis1 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction.Mitochondrial ultrastructure was evaluated by transmission electron microscopy.Compared with the sham group,apoptosis,Fis1 protein and mRNA expression and cytosolic cytochrome c levels in the cortical ischemic penumbra and cerebral infarct volume were increased after reperfusion in the other three groups.These changes caused by cerebral ischemia/reperfusion were inhibited in the hypothermia group compared with the normothermia group.These findings show that selective brain hypothermia inhibits Fis1 expression and reduces apoptosis,thereby ameliorating focal cerebral ischemia/reperfusion injury in rats.Experiments were authorized by the Ethics Committee of Qingdao Municipal Hospital of China (approval No.2019008).
基金supported by Scientific Research and Development Plan of Hebei Province,No.20276102DKey Project of Scientific Research in Universities of Hebei Province in China,No.ZD2010106
文摘Apolipoprotein E plays a crucial role in inhibiting chronic neurodegenerative processes. Howev-er, its impact on neurological function following diffuse brain injury is still unclear. This study was designed to evaluate the therapeutic effects and mechanisms of action of apolipoprotein E mimetic peptide on diffuse brain injury. Apolipoprotein E mimetic peptide was administered into the caudal vein of rats with diffuse brain injury before and after injury. We found that apo-lipoprotein E mimetic peptide signiifcantly decreased the number of apoptotic neurons, reduced extracellular signal-regulated kinase1/2 phosphorylation, down-regulated Bax and cytochrome c expression, decreased malondialdehyde content, and increased superoxide dismutase activity in a dose-dependent manner. These experimental ifndings demonstrate that apolipoprotein E mimetic peptide improves learning and memory function and protects against diffuse brain injury-induced apoptosis by inhibiting the extracellular signal-regulated kinase1/2-Bax mito-chondrial apoptotic pathway.
