Isoflurane Postconditioning Upregulates Phosphorylated Connexin 43 in the Middle Cerebral Artery Occlusion Model and Is Probably Associated with the TGF-<i>β</i>1/Smad2/3 Signaling Pathway

Yin, Jiangwen; Liu, Xuejiao; Ge, Ming; Xie, Liping; Zhai, Jingwen; Dai, Zhijun; Li, Yan; Wang, Sheng

doi:10.1155/2020/3451215

Cited by 8 publications

(5 citation statements)

References 38 publications

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“…Increasing evidence has demonstrated that anesthetic drugs, such as isoflurane and propofol, play vital roles in regulating molecular pathology changes in the central nervous system and neurocognitive behaviors. It is necessary to design a group of mice solely undergoing isoflurane anesthesia as a control to exclude drug interference in cognitive deficits postoperation [38,39,57]. Therefore, more experiments are still needed to confirm the effect of Smad7 in regulating the cognitive decline induced by anesthesia surgery in the future, which would provide an important theoretical basis for the molecular pathological mechanism and clinical intervention of cognitive impairment caused by anesthesia surgery.…”

Section: Discussionmentioning

confidence: 99%

“…All the mice were administered 50 μL of 0.2% ropivacaine subcutaneously for postoperative analgesia and then kept on a heating pad to recover spontaneously. All surgical procedures were completed within 10 min to reduce the impact of isoflurane, which has been confirmed to affect neurocognition by regulating signaling pathways [38,39]. Considering that anesthesia and surgery cannot be completely separated, the mice in the control group underwent neither anesthesia nor surgery.…”

Section: Anesthesia and Surgerymentioning

confidence: 99%

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Smad7 in the hippocampus contributes to memory impairment in aged mice after anesthesia and surgery

Liu

et al. 2023

J Neuroinflammation

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Background Postoperative cognitive dysfunction (POCD) is a common neurological complication following anesthesia and surgery. Increasing evidence has demonstrated that neuroinflammation caused by systemic inflammatory responses during the perioperative period is a key factor in the occurrence of POCD. In addition, SMAD family member 7 (Smad7) has been confirmed to play vital roles in the pathogenesis and treatment of inflammatory diseases, such as inflammatory bowel disease. However, whether Smad7 participates in the regulatory process of neuroinflammation and apoptosis in the development of POCD is still unknown. Methods In this study, a POCD mouse model was constructed by unilateral nephrectomy under anesthesia, and cognitive function was assessed using the fear conditioning test and open field test. The expression of Smad7 at the mRNA and protein levels in the hippocampus 3 days after surgery was examined by qRT-PCR, western blot and immunofluorescence assays. Furthermore, to identify whether the elevation of Smad7 in the hippocampus after unilateral nephrectomy contributes to cognitive impairment, the expression of Smad7 in the hippocampal CA1 region was downregulated by crossing Smad7fl/fl conditional mutant mice and CaMKIIα-Cre line T29-1 transgenic mice or stereotaxic injection of shRNA–Smad7. Inflammation and apoptosis in the hippocampus were assessed by measuring the mRNA levels of typical inflammatory cytokines, including TNF-α, IL-1β, IL-6, CCL2, CXCL1, and CXCL2, and the protein levels of apoptotic proteins, including Bax and Bcl2. In addition, apoptosis in the hippocampus postoperation was investigated by a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining assay. Finally, western blotting was used to explore how Smad7 mediates inflammation and apoptosis postoperation. Results The results unequivocally revealed that elevated Smad7 in the hippocampal CA1 region significantly inhibited TGF-β signal transduction by blocking Smad2/3 phosphorylation, which enhanced neuroinflammation and apoptosis in the hippocampus and further led to learning and memory impairment after surgery. Conclusions Our results revealed that Smad7 contributes to cognitive impairment after surgery by enhancing neuroinflammation and apoptosis in the hippocampus and might serve as a promising therapeutic target for the treatment of memory impairment after anesthesia surgery.

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Section: Discussionmentioning

confidence: 99%

Section: Anesthesia and Surgerymentioning

confidence: 99%

Smad7 in the hippocampus contributes to memory impairment in aged mice after anesthesia and surgery

Liu

et al. 2023

J Neuroinflammation

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“…PDCD4 expression is not only regulated by miR-21-5p, but also at the level of transcription, translation and protein degradation [25], therefore mechanisms influenced by isoflurane with opposing effects than miR-21-5p could be responsible for maintaining the PCDC4 expression. For example, isoflurane is able to increase transforming growth factor beta-1 (TGF-β1) levels [26], which in turn induces apoptosis via PDCD4 overexpression [25].…”

Section: Discussionmentioning

confidence: 99%

MiR-21-5p but not miR-1-3p expression is modulated by preconditioning in a rat model of myocardial infarction

et al. 2020

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Isoflurane (Iso) preconditioning (PC) is known to be cardioprotective against ischemia/reperfusion (I/R) injury. It was previously shown that microRNA-21-5p (miR-21-5p) is regulated by Iso-PC. It is unclear, if expression of cardiac enriched miR-1-3p is also affected by Iso-PC, and associated with activation of HIF1α (hypoxia-inducible factor 1-alpha). Male Wistar rats (n = 6–8) were randomly assigned to treatment with or without 1 MAC Iso for 30 min, followed by 25 min of regional myocardial ischemia, with 120 min reperfusion. At the end of reperfusion, myocardial expression of miR-1-3p, miR-21-5p and mRNAs of two HIF-1α-dependent genes, VEGF (vascular endothelial growth factor) and HO-1 (heme oxygenase-1), were determined by quantitative PCR. Protein expression of a miR-21 target gene, PDCD4 (programmed cell death protein 4), was assessed by western blot analysis. Infarct sizes were analyzed with triphenyltetrazoliumchloride staining. MiR-21-5p expression was increased by Iso, whereas expression of miR-1-3p was not altered. The expression of VEGF but not HO-1 was induced by Iso. Iso-PC reduced infarct sizes compared to untreated controls. No regulation of miRNA and mRNA expression was detected after I/R. PDCD4 protein expression was not affected after Iso exposure. Expression of miR-21-5p, in contrast to miR-1-3p, is altered during this early time point of Iso-PC. HIF1α signaling seems to be involved in miR-21-5p regulation.

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“…Post-injury conditioning was investigated with a range of stimuli. Iso urane post-conditioning (for 60 minutes immediately post-MCAO) was shown to reduce neurological severity score (NSS), infarct volume and neuronal survival or density in a TGF-β1-dependent manner [103][104][105] . Remote ischemic postconditioning generated an increase in TGF-β1 expression and phosphorylation of Smad2/3 which correlated with reduced infarct volume and improved NSS, con rmed by TGF-β1 knockdown 106 .…”

Section: Tgf-β1 In Pre-clinical Ischemic Stroke Studiesmentioning

confidence: 99%

The double-edged sword of transforming growth factor β 1: a systematic review of pre-clinical stroke models

Hewitt,

Ali,

Hubbard

et al. 2024

Preprint

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Stroke is a leading cause of death, with those that survive often suffering significant disability. Strokes are classified as ischemic, occlusion of a blood vessel leading to reduction in cerebral blood flow, or hemorrhagic, the rupture of a vessel causing bleeding into the brain. Transforming growth factor beta 1 (TGF-β1), a pleiotropic cytokine, has been investigated in stroke due to its wide-ranging effects on proliferation, extracellular matrix deposition and inflammation. This systematic review examined the role of TGF-β1 in pre-clinical studies of both ischemic and hemorrhagic stroke. A search was performed across PubMed, Web of Science and Scopus, including English-language animal studies which examined TGF-β1 signaling as an outcome or intervention. 89 studies were ultimately included: 68 ischemic and 21 hemorrhagic stroke. Studies were assessed for bias following the SYRCLE guidelines for pre-clinical studies, followed by extraction of the methodology and the role of TGF-β1. Compliance with SYRCLE guidelines was found to be low and the methodological approaches for creating stroke models were variable. A range of interventions were shown to modify TGF-β1 expression or signaling, with exogenous TGF-β1 improving outcomes in all included ischemic stroke studies. TGF-β1 was found to play a protective role in 76% of ischemic stroke studies whereas it was only protective in 33% of hemorrhagic stroke studies, with likely involvement in fibrosis development in the latter. Our findings suggest a marked difference in the function of TGF-β1 between these types of stroke, and it is hypothesized that blood cytotoxicity following hemorrhagic stroke may generate a more sustained expression of TGF-β1 than seen in ischemic stroke. This may lead to TGF-β1 mediated fibrosis and post-hemorrhagic hydrocephalus, as opposed to the neuroprotective role played by the same molecule following ischemic stroke. These findings highlight the possible clinical utility of exogenous TGF-β1 therapies after ischemic stroke, and TGF-β1 inhibitors after hemorrhagic stroke, to reduce morbidity and disability caused by these events.

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Isoflurane Postconditioning Upregulates Phosphorylated Connexin 43 in the Middle Cerebral Artery Occlusion Model and Is Probably Associated with the TGF-β1/Smad2/3 Signaling Pathway

Cited by 8 publications

References 38 publications

Smad7 in the hippocampus contributes to memory impairment in aged mice after anesthesia and surgery

Smad7 in the hippocampus contributes to memory impairment in aged mice after anesthesia and surgery

MiR-21-5p but not miR-1-3p expression is modulated by preconditioning in a rat model of myocardial infarction

The double-edged sword of transforming growth factor β 1: a systematic review of pre-clinical stroke models

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