Astrocytic endothelin-1 overexpression promotes neural progenitor cells proliferation and differentiation into astrocytes via the Jak2/Stat3 pathway after stroke

Cheng, Xiuyuan; Yeung, Patrick Ka Kit; Zhong, Kuangbiao; Zilundu, Prince L M; Zhou, Lihua; Chung, Sookja K.

doi:10.1186/s12974-019-1597-y

Cited by 51 publications

(34 citation statements)

References 70 publications

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“…In addition, our study showed that the phosphorylation levels of JAK2/STAT3 are downregulated after IR injury, while pretreatment with mild hypothermia and leptin can upregulate these and thus attenuate IR injury; these results confirmed that activating JAK2/-STAT3 pathway can attenuate IR injury. However, our results are in dispute with some studies, which showed that the phosphorylation levels of JAK2/STAT3 are increased after IR injury [51][52][53]. We think it has something to do with the time of the models.…”

Section: Discussioncontrasting

confidence: 99%

Mild Hypothermia Attenuates Hepatic Ischemia–Reperfusion Injury through Regulating the JAK2/STAT3-CPT1a-Dependent Fatty Acid β-Oxidation

Wang

Xia

et al. 2020

Oxidative Medicine and Cellular Longevity

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Hepatic ischemia–reperfusion (IR) injury is a clinical issue that can result in poor outcome and lacks effective therapies at present. Mild hypothermia (32–35°C) is a physiotherapy that has been reported to significantly alleviate IR injury, while its protective effects are attributed to multiple mechanisms, one of which may be the regulation of fatty acid β-oxidation (FAO). The aim of the present study was to investigate the role and underlying mechanisms of FAO in the protective effects of mild hypothermia. We used male mice to establish the experimental models as previously described. In brief, before exposure to in situ ischemia for 1 h and reperfusion for 6 h, mice received pretreatment with mild hypothermia for 2 h and etomoxir (inhibitor of FAO) or leptin (activator of FAO) for 1 h, respectively. Then, tissue and blood samples were collected to evaluate the liver injury, oxidative stress, and changes in hepatic FAO. We found that mild hypothermia significantly reduced the hepatic enzyme levels and the score of hepatic pathological injury, hepatocyte apoptosis, oxidative stress, and mitochondrial injury. In addition, the expression of the rate-limiting enzyme (CPT1a) of hepatic FAO was downregulated almost twofold by IR, while this inhibition could be significantly reversed by mild hypothermia. Experiments with leptin and etomoxir confirmed that activation of FAO could also reduce the hepatic enzyme levels and the score of hepatic pathological injury, hepatocyte apoptosis, oxidative stress, and mitochondrial injury induced by IR, which had the similar effects to mild hypothermia, while inhibition of FAO had negative effects. Furthermore, mild hypothermia and leptin could promote the phosphorylation of JAK2/STAT3 and upregulate the ratio of BCL-2/BAX to suppress hepatocyte apoptosis. Thus, we concluded that FAO played an important role in hepatic IR injury and mild hypothermia attenuated hepatic IR injury mainly via the regulation of JAK2/STAT3-CPT1a-dependent FAO.

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Section: Discussioncontrasting

confidence: 99%

Mild Hypothermia Attenuates Hepatic Ischemia–Reperfusion Injury through Regulating the JAK2/STAT3-CPT1a-Dependent Fatty Acid β-Oxidation

Wang

Xia

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…Increased neuronal connectivity is considered to be one of the conditions that promote functional recovery following SCI ( 48 ). These results suggested that the STAT3-RNAi-transfected NSCs produced highly developed neurons that served a potentially useful role in neurogenesis, consistent with the results of previous studies ( 14 , 23 ). Wu et al ( 49 ) used microRNA-15a to downregulate STAT3 in mice following SCI, following which a superior functional recovery was observed.…”

Section: Discussionsupporting

confidence: 92%

“…Immunofluorescence staining analysis showed that the targeted inhibition of STAT3 induced the differentiation of NSCs into neurons, as the neuronal marker β3-tubulin ( 24 ) was found to be expressed more frequently in the LV-STAT3 group compared with that in the CL and LV-CL groups. However, GFAP, a specific marker of astrocytes ( 23 ), was expressed at significantly lower levels in the LV-STAT3 group compared with those in the other two groups ( Fig. 1E-G ).…”

Section: Resultsmentioning

confidence: 91%

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Targeted inhibition of STAT3 in neural stem cells promotes neuronal differentiation and functional recovery in rats with spinal cord injury

Zhao

Duan

et al. 2021

Exp Ther Med

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STAT3 is expressed in neural stem cells (NSCs), where a number of studies have previously shown that STAT3 is involved in regulating NSC differentiation. However, the possible molecular mechanism and role of STAT3 in spinal cord injury (SCI) remain unclear. In the present study, the potential effect of STAT3 in NSCs was first investigated by using short hairpin RNA (shRNA)-mediated STAT3 knockdown in rat NSCs in vitro . Immunofluorescence of β3-tubulin and glial fibrillary acidic protein staining and western blotting showed that knocking down STAT3 expression promoted NSC neuronal differentiation, where the activity of mTOR was upregulated. Subsequently, rats underwent laminectomy and complete spinal cord transection followed by transplantation of NSCs transfected with control-shRNA or STAT3-shRNA at the injured site in vivo . Spinal cord-evoked potentials and the Basso-Beattie-Bresnahan scores were used to examine functional recovery. In addition, axonal regeneration and tissue repair were assessed using retrograde tracing with FluoroGold, hematoxylin and eosin, Nissl and immunofluorescence staining of β3-tubulin, glial fibrillary acidic protein and microtubule-associated protein 2 following SCI. The results showed that transplantation with NSCs transfected with STAT3-RNA enhanced functional recovery following SCI and promoted tissue repair in rats, in addition to improving neuronal differentiation of the transplanted NSCs in the injury site. Taken together, in vitro and in vivo evidence that inhibiting STAT3 could promote NSC neuronal differentiation was demonstrated in the present study. Therefore, transplantation with NSCs with STAT3 expression knocked down appears to hold promising potential for enhancing the benefit of NSC-mediated regenerative cell therapy for SCI.

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“…Astrocytes are the main type of glial cells, accounting for more than 50% of the total volume of brain cells. ET-1 produced by activated astrocytes binds to its cognate receptor expressed on astrocytes and causes neuroinflammation [ 14 ], potentiated by increased expression of matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor-A (VEGF-A) in astrocytes, ultimately resulting in brain edema [ 15 ]. In this study, we investigated whether UTI alleviates the severity of TBI by suppressing the astrocyte activity and limiting the production of ET-1 and inflammatory mediators.…”

Section: Introductionmentioning

confidence: 99%

Ulinastatin alleviates traumatic brain injury by reducing endothelin-1

Liu

Liao

Zhou

2020

Translational Neuroscience

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Background Brain edema is one of the major causes of fatality and disability associated with injury and neurosurgical procedures. The goal of this study was to evaluate the effect of ulinastatin (UTI), a protease inhibitor, on astrocytes in a rat model of traumatic brain injury (TBI). Methodology A rat model of TBI was established. Animals were randomly divided into 2 groups – one group was treated with normal saline and the second group was treated with UTI (50,000 U/kg). The brain water content and permeability of the blood–brain barrier were assessed in the two groups along with a sham group (no TBI). Expression of the glial fibrillary acidic protein, endthelin-1 (ET-1), vascular endothelial growth factor (VEGF), and matrix metalloproteinase 9 (MMP-9) were measured by immunohistochemistry and western blot. Effect of UTI on ERK and PI3K/AKT signaling pathways was measured by western blot. Results UTI significantly decreased the brain water content and extravasation of the Evans blue dye. This attenuation was associated with decreased activation of the astrocytes and ET-1. UTI treatment decreased ERK and Akt activation and inhibited the expression of pro-inflammatory VEGF and MMP-9. Conclusion UTI can alleviate brain edema resulting from TBI by inhibiting astrocyte activation and ET-1 production.

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Astrocytic endothelin-1 overexpression promotes neural progenitor cells proliferation and differentiation into astrocytes via the Jak2/Stat3 pathway after stroke

Cited by 51 publications

References 70 publications

Mild Hypothermia Attenuates Hepatic Ischemia–Reperfusion Injury through Regulating the JAK2/STAT3-CPT1a-Dependent Fatty Acid β-Oxidation

Mild Hypothermia Attenuates Hepatic Ischemia–Reperfusion Injury through Regulating the JAK2/STAT3-CPT1a-Dependent Fatty Acid β-Oxidation

Targeted inhibition of STAT3 in neural stem cells promotes neuronal differentiation and functional recovery in rats with spinal cord injury

Ulinastatin alleviates traumatic brain injury by reducing endothelin-1

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