Sevoflurane Pretreatment Research Articles

Protective effect of sevoflurane on myocardial ischemia-reperfusion injury: a systematic review and meta-analysis.

Myocardial ischemia-reperfusion (I/R) injury significantly impacts recovery in both cardiac and non-cardiac surgeries, potentially leading to severe cardiac dysfunction. Sevoflurane, a volatile anesthetic, is reputed for its protective effects against myocardial I/R injury, although evidence remains inconclusive. This systematic review and meta-analysis aim to clarify the cardioprotective efficacy of sevoflurane. The systematic search of databases including Medline, Embase, Scopus, and Web of Science, was supplemented with a manual search to retrieve studies using rat or mouse models of myocardial I/R injury, comparing sevoflurane pretreatment (≥ 24 hours before I/R), preconditioning (within 24 hours before I/R), or post-conditioning (after I/R) against non-treated controls. The outcomes were cardiac function, myocardial infarct size, apoptosis, inflammation, oxidative stress, and cardiac biomarkers. Using the random effects model, standardized mean differences (SMD) were pooled to perform meta-analyses. Fifty-one studies, encompassing 8189 subjects, were included in the meta-analysis. Pretreatment with Sevoflurane significantly reduced infarct size. Sevoflurane preconditioning exhibited positive effects on left ventricular parameters and ejection fraction, and reduced infarct size, apoptosis, and oxidative stress. Post-conditioning with Sevoflurane demonstrated improvements in cardiac function, including enhanced left ventricular parameters and reduced infarct size, apoptosis, inflammation, oxidative stress, and cardiac biomarkers. Sevoflurane demonstrates a significant protective effect against myocardial I/R injury in animal models. These findings support the potential clinical utility of sevoflurane as an anesthetic choice in preventing and managing myocardial I/R injury during surgeries.

Sevoflurane Confers Protection Against the Malignant Phenotypes of Lung Cancer Cells via the microRNA-153-3p/HIF1α/KDM2B Axis.

Sevoflurane is shown to curtail lung cancer (LC) development. Herein, this research sought to investigate the underlying mechanism of sevoflurane in regard to its repressive effects on LC. Expression levels of microRNA (miR)-153-3p, HIF1α, and KDM2B in LC tissues and cells were determined with qRT-PCR. Following sevoflurane pretreatment and/or ectopic expression and knockdown experiments, the malignant phenotypes, and levels of miR-153-3p, HIF1α, and KDM2B in LC A549 cells were detected using Transwell, scratch, EdU, CCK-8, Western blot, and qRT-PCR assays. Relationship between HIF1α and miR-153-3p was verified with a dual-luciferase reporter assay. The interaction between HIF1α and KDM2B was verified with a ChIP assay. LC tissues and cells presented low miR-153-3p expression and high HIF1α and KDM2B expression. Sevoflurane pretreatment, miR-153-3p upregulation, HIF1α downregulation, or KDM2B downregulation impeded the malignant phenotypes of A549 cells. Sevoflurane pretreatment augmented miR-153-3p expression, while miR-153-3p negatively targeted HIF1α. HIF1α bound to the KDM2B promoter to upregulate KDM2B. HIF1α or KDM2B overexpression counteracted the inhibitory effects of sevoflurane pretreatment on A549 cell malignant behaviors. Sevoflurane decreased HIF1α expression through upregulation of miR-153-3p, thereby reducing KDM2B transcription to restrict the malignant phenotypes of LC A549 cells.

Neuroprotective effect of ketamine and sevoflurane against TNF-α induced cognitive impairment.

In the present study, neuroprotective effect of sevoflurane in combination with ketamine was investigated on TNF-α induced necroptosis of neurons and cognitive impairment in the rat model. The results demonstrated that exposure to TNF-α/z-VAD led to a significant decrease in viability of HT-22 neuronal cells. However, incubation of HT-22 cells with ketamine plus sevoflurane inhibited decrease in viability induced by TNF-α/z-VAD exposure. The increase in production of ROS by TNF-α/z-VAD exposure in HT-22 cells was effectively suppressed on pre-treatment with ketamine plus sevoflurane. Moreover, suppression of TNF-α/z-VAD induced ROS production in HT-22 cells by ketamine plus sevoflurane pretreatment was higher in comparison to ketamine or sevoflurane treatment alone. Treatment of HT-22 cells with ketamine plus sevoflurane suppressed TNF-α/z-VAD induced increase in RIP1 and p-MLKL protein expression. Ketamine plus sevoflurane treatment effectively reversed decrease in movement speed as well as total distance traveled in TNF-α injected rats. The number of neurons in rat hippocampus injected with TNF-α showed a significant decrease more specifically in carbonic anhydrase-3 region. However, no significant change in the density of neurons was observed in the hippocampus of rats pretreated with ketamine plus sevoflurane by TNF-α injection. The increase in expression of p-MLKL and p-RIP3 by TNF-α injection was effectively reversed in rats on treatment with ketamine plus sevoflurane. In silico studies revealed that ketamine interacts with p-MLKL protein in different confirmations with the binding affinities ranging from -9.7 to -8.4 kcal/mol. It was found that ketamine binds to p-MLKL protein by interacting with alanine (ALA A:295), proline (PRO A:306), glutamine (GLN A: 307) and isoleucine (ILE A:293) amino acid residues. In summary, ketamine plus sevoflurane combination alleviates TNF-α/z-VAD induced decrease in viability of HT-22 cells in vitro and rat hippocampus neurons in vivo. Moreover, ketamine plus sevoflurane combination prevented TNF-α injection induced cognitive impairment in rats. Therefore, sevoflurane plus ketamine combination can be developed as a potential therapeutic regimen for treatment of isoflurone induced cognitive impairment.

Sevoflurane participates in the protection of rat renal ischemia-reperfusion injury by down-regulating the expression of TRPM7.

To investigate the protective effect of sevoflurane preconditioning on renal ischemia-reperfusion injury (renalischemiareperfusionmodel, RIRI) and its related mechanism. Eighty healthy adult male SD rats were randomly divided into control group (Sham group), model group (RIRI group), sevoflurane pretreatment group (Sev group) and TRPM7 inhibitor combined with sevoflurane pretreatment group (T + Sev group), 20 animals in each group. Hematoxylin-eosin (HE) staining was used to observe the pathological changes of renal tissue, and the levels of creatinine and urea nitrogen in each group were detected. Deoxyribonucleic acid terminal transferase-mediated dUTP nick end labeling (TUNEL) assay was used to detect renal cell apoptosis, and Western blottingwas used to detect the expression of apoptotic proteins cleaved-caspase-3, bax, Bcl-2, and TRPM7 in renal tissue; Detection of oxidative stress-related index levels in renal tissue and levels of inflammatory factors in renal tissue and serum. Compared with the Sham group, the renal tissue pathological damage was aggravated, the levels of creatinine and blood urea nitrogen were increased, and the apoptosis was increased in the RIR group and the Sev group. Death, malondialdehyde (MDA) levels and inflammatory factors were increased, and superoxide dismutase (SOD) levels were decreased (all p < .05); The scores, apoptosis rate, MDA level, and relative expression of inflammatory factor levels were decreased, and SOD levels were increased (all p < .05). Compared with the Sev group, the renal tissue pathological damage in the T + Sev group was aggravated, creatinine, blood urea nitrogen levels increased, apoptosis increased, apoptosis-related proteins cleaved-caspase-3, bax, Bcl-2 showed increased apoptosis, malondialdehyde (MDA) levels, inflammatory factor levels increased, ultrahigh The levels of oxide dismutase (SOD) were decreased (all p < .05). Therefore, we believe that sevoflurane is involved in the protection of rat renal ischemia-reperfusion injury by downregulating the expression of TRPM7.

Molecular Mechanism of Sevoflurane Preconditioning Based on Whole-transcriptome Sequencing of Lipopolysaccharide-induced Cardiac Dysfunction in Mice.

Sevoflurane, a widely used inhalation anesthetic, has been shown to be cardioprotective in individuals with sepsis and myocardial dysfunction. However, the exact mechanism has not been completely explained. In this study, we performed whole-transcriptome profile analysis in the myocardium of lipopolysaccharide-induced septic mice after sevoflurane pretreatment. RNA transcriptome sequencing showed that 97 protein coding RNAs (mRNAs), 64 long noncoding RNAs (lncRNAs), and 27 microRNAs (miRNAs) were differentially expressed between the lipopolysaccharide and S_L groups. Functional enrichment analysis revealed that target genes for the differentially expressed mRNAs between the 2 groups participated in protein processing in the endoplasmic reticulum, antigen processing and presentation, and the mitogen-activated protein kinase signaling pathway. The bioinformatics study of differentially expressed mRNAs revealed that 13 key genes including Hsph1, Otud1, Manf, Gbp2b, Stip1, Gbp3, Hspa1b, Aff3, Med12, Kdm4a, Gatad1, Cdkn1a, and Ppp1r16b are related to the heart or inflammation. Furthermore, the competing endogenous RNA network revealed that 3 of the 13 key genes established the lncRNA-miRNA-mRNA network (ENSMUST00000192774 --- mmu-miR-7a-5p --- Hspa1b, TCONS_00188587 --- mmu-miR-204-3p --- Aff3 and ENSMUST00000138273 --- mmu-miR-1954 --- Ppp1r16b) may be associated with cardioprotection in septic mice. In general, the findings identified 11 potential essential genes (Hsph1, Otud1, Manf, Gbp2b, Stip1, Gbp3, Hspa1b, Aff3, Med12, Kdm4a, Gatad1, Cdkn1a, and Ppp1r16b) and mitogen-activated protein kinase signaling pathway involved in sevoflurane-induced cardioprotection in septic mice. In particular, sevoflurane may prevent myocardial injury by regulating the lncRNA-miRNA-mRNA network, including (ENSMUST00000192774-mmu-miR-7a-5p-Hspa1b, TCONS_00188587-mmu-miR-204-3p-Aff3, and ENSMUST00000138273-mmu-miR-1954-Ppp1r16b networks), which may be a novel mechanism of sevoflurane-induced cardioprotection.

Sevoflurane pretreatment regulates abnormal expression of MicroRNAs associated with spinal cord ischemia/reperfusion injury in rats.

BackgroundSpinal cord ischemia/reperfusion injury (SCII) is one of the most serious spinal cord complications that stem from varied spine injuries or thoracoabdominal aortic surgery. Nevertheless, the molecular mechanisms underlying the SCII remain unclear.MethodsMale Sprague-Dawley (SD) rats were randomly divided into 5 groups of sham, SCII 24 h, SCII 72 h, sevoflurane preconditioning SCII 24 h (SCII 24 h+sevo), and sevoflurane preconditioning SCII 72 h (SCII 72 h+sevo) group. We then analyzed the expression of differentially expressed micro RNAs (DEmiRNAs) in these groups and their target genes. Functional enrichment analysis of their target genes was further performed using Metascape software. The microRNA-messenger RNA-pathway (miRNA-mRNA-pathway) network and the sevoflurane-miRNA-mRNA-pathway integrative network were further constructed to explore the molecular mechanisms underlying SCII and neuroprotective effects of sevoflurane against SCII. Molecular docking was also performed to evaluate the interactions between hub targets and sevoflurane. Finally, the expression levels of miR-21-5p and its target genes [mitogen-activated protein kinase kinase 3 and protein phosphatase 1 regulatory subunit 3B (MAP2K3 and PPP1R3B)] were measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analyses.ResultsWe found that sevoflurane alters several miRNA expression following SCII at 24 and 72 h after reperfusion. It was shown that miR-221-3p, miR-181a-1-3p, and miR-21-5p were upregulated both at 24 and 72 h in the sevoflurane pre-treatment reperfusion groups. Functional enrichment analysis revealed that target genes for the above co-DEmiRNAs at 24 and 72 h in the SCII group with sevoflurane pretreatment participated in the mitogen-activated protein kinase (MAPK), ErbB, apoptosis, and transforming growth factor-beta (TGF-beta) signaling pathways. Both MAP2K3 and PPP1R3B were found to be common targets for sevoflurane and miRNA-mRNA-pathway (rno-miR-21-5p). It was shown that MAP2K3 regulates the MAPK signaling and the T cell receptor signaling pathways, whereas PPP1R3B regulates the ErbB signaling pathway. Molecular docking further revealed that sevoflurane strongly binds the MAP2K3 and PPP1R3B proteins. Compared to the sham group, SCII induced significant under-expression of miR-21-5p but upregulated PPP1R3B and MAP2K3 proteins; sevoflurane pretreatment increased the expression of miR-21-5p but decreased those of PPP1R3B and MAP2K3 proteins.ConclusionsIn general, sevoflurane regulates the expression of several miRNAs following SCII. In particular, sevoflurane might protect against SCII via regulating the expression of miR-21-5p, its target genes (MAP2K3 and PPP1R3B), and related signaling pathways.

Sevoflurane protects the liver from ischemia-reperfusion injury by regulating Nrf2/HO-1 pathway

We aimed to investigate the role and mechanism of sevoflurane (SEV) preconditioning in liver ischemia-reperfusion (I/R) injury. In vivo, rats were randomly divided into Sham group, I/R rat model group, I/R + SEV group and SEV group. In vitro, hypoxia-reoxygenation (H/R) cell model were established. Hematoxylin-Eosin (H&E) and TUNEL assay were used to evaluate the degree of tissue damage and detect apoptosis in rats, respectively. HO-1, nuclear Nrf2 and cytosolic Nrf2 expressions were detected by immunohistochemical staining, Western blot analysis and quantitative real-time PCR (qRT-PCR), respectively. Contents of Lactate dehydrogenase (LDH), malondialdehyde (MDA), and reactive oxygen species (ROS) were determined by corresponding kits. Inflammatory factor levels, cell viability, apoptosis were detected by enzyme-linked immunosorbent assay (ELISA), MTT assay, and flow cytometry, respectively.In the I/R group, liver damage was severe, apoptosis-positive cells were increased, HO-1 and nuclear Nrf2 expressions were increased, and cytosolic Nrf2 expression was decreased. After SEV pretreatment, the degree of liver injury and apoptosis in rats were significantly reduced, HO-1 and nuclear Nrf2 expressions were increased significantly, and cytosolic Nrf2 expression was decreased. 4% SEV had the best mitigating effect on H/R-induced liver cell damage, as evidenced by reduced contents of LDH and MDA, decreased inflammatory factors, a lowered apoptosis rate, inhibited ROS production, effectively promoted Nrf2 nucleation, and activated Nrf/HO-1 pathway. ML385 pretreatment significantly inhibited the effect of SEV on hepatocytes.Sevoflurane protects the liver from ischemia-reperfusion injury by regulating the Nrf2/HO-1 pathway.

Sevoflurane ameliorates adriamycin-induced myocardial injury in rats through the PI3K/Akt/GSK-3β pathway.

The aim of this study was to explore the effects of sevoflurane (SEV) pretreatment on Adriamycin (ADR)-induced myocardial injury through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) pathway. A total of 24 rats weighing 200-250 g were divided into four groups, including: control group (C group), ADR injection group (ADR group), SEV pretreatment group (ADR + SEV group) and inhibitor group (ADR + SEV + LY group). H9c2 cells were cultured in vitro and were divided into control group (C group), ADR treatment group (ADR group), and SEV pretreatment group (ADR + SEV group) and inhibitor group (ADR + SEV + LY group) as well. Next, the content of aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and creatine kinase (CK) in the serum was detected via Enzyme-Linked Immunosorbent Assay (ELISA). Hematoxylin-eosin (HE) staining assay was performed to determine the severity of myocardial injury. Meanwhile, the apoptosis rate of cells was detected through terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) assay. Additionally, Western blotting (WB) was employed to measure the protein expression levels of phosphorylated (p)-GSK-3β, p-PI3K, Akt and p-Akt. Compared with C group, ADR significantly increased the content of AST, LDH and CK in the serum (p<0.01), reduced protein expression levels of p-GSK-3β, p-PI3K and p-Akt (p<0.01), increased apoptosis rate (p<0.01), and induced myocardial injury. SEV pretreatment significantly alleviated the effect of ADR, manifested as significantly lowered content of AST, LDH and CK in the serum (p<0.01), distinctly elevated protein expression levels of p-GSK-3β, p-PI3K and p-Akt (p<0.01), notably reduced apoptosis rate (p<0.01), and relieved myocardial injury. LY294002 remarkably inhibited the protective effect of SEV against myocardial injury (p<0.01) CONCLUSIONS: SEV is able to prominently ameliorate ADR-induced myocardial injury by regulating the phosphorylation level of the PI3K/Akt/GSK-3β signaling pathway.

Volatile anesthetic sevoflurane pretreatment alleviates hypoxia-induced potentiation of excitatory inputs to striatal medium spiny neurons of mice.

Sevoflurane, a commonly used anesthetic in surgery, has drawn attention because of its preconditioning effects in hypoxic conditions. To investigate the preconditioning effects in the striatum, a common site for ischemic stroke, we collected whole-cell current-clamp recordings from striatal medium spiny neurons. In our in vitro brain slice experiments, deprivation of oxygen and glucose depolarized the striatal neurons to subthreshold potentials, and the pre-administration of sevoflurane (4%, 15min) prolonged the time to depolarization. Furthermore, transient hypoxia induced the potentiation of excitatory postsynaptic potentials, which play a part in post-ischemic excitotoxicity. Glibenclamide, a KATP channel inhibitor, reversed the prolonged time to depolarization and the prevention of the pathological potentiation of excitatory responses, indicating that the short exposure to sevoflurane likely participates in neuroprotection against hypoxia via activation of KATP channels. A monocarboxylate transporter blocker, 4-CIN, also depolarized striatal neurons. Interestingly, the blockade of monocarboxylate transporters that supply lactate to neurons caused the pathological potentiation, even in the presence of enough oxygen and glucose. In this case, sevoflurane could not prevent the pathological potentiation, suggesting the involvement of monocarboxylate transporters in the sevoflurane-mediated effects. These results indicate that sevoflurane protects striatal neurons from hypoxic damage and alleviates the pathological potentiation. Under these conditions, sevoflurane may become an effective intervention for patients undergoing surgery.

Effect of sevoflurane pretreatment on myocardial ischemia-reperfusion injury in diabetic rats and the relationship with ERK1/2 signaling pathway

Effect of sevoflurane pretreatment on myocardial ischemia-reperfusion injury in diabetic rats and the relationship with ERK1/2 signaling pathway

Study on the Protective Effect of Sevoflurane on H2O2-Induced HK-2 Cells

Background: Renal ischemia reperfusion injury (RIRI) is the main cause of acute kidney injury (AKI). The aim of this study was to investigate whether sevoflurane could protect HK-2 cells treated by H2O2 by improving apoptosis and oxidative stress through TLR4/MyD88/NF-κb signaling pathway. Methods: HK-2 cells was treated with H2O2 to construct the oxidative damage model happened in renal ischemia reperfusion injury (RIRI). CCK-8 assay was performed to analyze the viability of HK-2 cells. The reactive oxygen species (ROS), lactate dehydrogenase (LDH), superoxide dismutase (SOD) and malondialdelyde (MDA) testing kits were used for the detection of oxidative stress related factors. TUNEL assay and Western blot were applied to analyze the apoptosis of HK-2 cells. And, proteins of TLR4/MyD88/NF-κb signaling pathway were also detected by western blot. Results: The viability of H2O2-induced HK-2 cells was decreased compared with the control group. The ROS, SOD and MDA levels were increased and LDH level was decreased in H2O2-induced HK-2 cells. The apoptosis of H2O2-induced HK-2 cells was increased. The expression of Bax was decreased and the expression of Bcl-2 and cleaved caspase 3 were increased in the H2O2-induced HK-2 cells. The expression of TLR4/MyD88/NF-κb signaling pathway was increased in the H2O2-induced HK-2 cells. All these changes were reversed by pretreatment with sevoflurane to some extent in HK-2 cells. Conclusion: In conclusion, sevoflurane pretreatment protects HK-2 cells treated by H2O2 by improving apoptosis and oxidative stress through inhibiting the TLR4/MyD88/NF-κb signaling pathway.

Sevoflurane pretreatment attenuates hypoxia/reoxygenation-induced cardiomyocyte apoptosis through activation of AKT/pim-1 and AKT/GSK3β signaling pathways

Myocardial ischemia-reperfusion injury (IRI) is a severe trauma which is characterized by inflammatory reaction, oxidative stress and cardiomyocyte apoptosis. Anesthetics such as sevoflurane have been proved to exhibit cardioprotective effect on IRI and the present study aimed to explore the underlying mechanism. In this study, H9C2 cells were randomly divided into the following groups: Control group; hypoxia/reoxygenation (H/R) group; 2.5% sevoflurane (Sev) 1 h group (H9C2 cells were exposed to 1 h of 2.5% sevoflurane 24 h before H/R); 2.5% Sev 2 h group (H9C2 cells were exposed to 2 h of 2.5% sevoflurane 24 h before H/R); 2.5% sevoflurane (Sev) 2 h + LY294002 group (H9C2 cells were pretreated with 10 μL LY294002 for 24 h before sevoflurane treatment). Cell proliferation and apoptosis were examined by CCK8 assay and Flow cytometry. Then, the expression levels of key proteins, including Bcl-2, Mcl-1, iNOS, p-AKT, t-AKT, PIM1, P-Bad, p-GSK3β, t-GSK3β and cyclinD1, were examined by western blot. Furthermore, nitric oxide (NO) concentration was detected with an ELISA kit, and TNF-α, IL-1β, IL-6 and IL-10 levels were examined by western blot. The CCK8 assay and flow cytometry results indicated that sevoflurane pretreatment reduced the apoptosis of H9C2 cells with H/R injury. In addition, sevoflurane pretreatment significantly inhibited the inflammatory injury induced by H/R. Furthermore, sevoflurane activated AKT/Pim-1 and AKT/GSK3β signaling pathway. These beneficial effects of sevoflurane were canceled by phosphoinositide-3-kinase inhibitor LY294002. In conclusion, these results verified that sevoflurane attenuates H/R-induced cardiomyocyte injury via AKT/Pim-1 and AKT/GSK3β signaling pathways.

Effect of sevoflurane pretreatment in relieving liver ischemia/reperfusion-induced pulmonary and hepatic injury.

Purpose To investigate the effect of sevoflurane preconditioning on ischemia/reperfusion (I/R)-induced pulmonary/hepatic injuryMethods Fifty-one Wistar rats were randomly grouped into sham, I/R, and sevoflurane groups. After reperfusion, the structural change of the lung was measured by Smith score, the wet and dry weights (W/D) were determined, malondialdehyde (MDA) myeloperoxidase (MPO) content was determined colorimetrically and by fluorescence, respectively, and matrix metalloprotein-9 (MMP-9) mRNA was quantified by RT-PCR. Biopsy and morphological analyses were performed on liver tissue, activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were determined, and tumor necrosis factor-alpha (TNF-α) level was determined.Results The sham group showed no changes in tissue structure. Structural lesions in the sevoflurane and I/R groups were mild and severe, respectively. Smith score, W/D, MDA, MPO, and MMP mRNA showed the same trend, and were increased in the I/R group and recovered in the sevoflurane group, compared with the sham group (both P<0.05). AST and ALT were significantly increased compared to the sham group (AST: 655±52.06 vs . 29±9.30 U/L; ALT: 693±75.56 vs . 37±6.71 U/L; P<0.05). In the sevoflurane group, AST and ALT levels were significantly decreased (464±47.71 and 516±78.84 U/L; P<0.001). TNF-α presented similar results.Conclusion The protection of lung and liver by sevoflurane may be mediated by inhibited leukocyte recruitment and MMP-9 secretion.

MicroRNA-874 inhibition targeting STAT3 protects the heart from ischemia-reperfusion injury by attenuating cardiomyocyte apoptosis in a mouse model.

MicroRNAs (miRs) were involved in numerous cardiovascular diseases, especially ischemic heart diseases, but the miR changes during cardiac ischemia-reperfusion (I/R) injury following sevoflurane (SEV) preconditioning are still unknown. This study aims to investigate the effect of miR-874 on cardiac I/R injury in mouse models pretreated with SEV. Following establishment of mouse models with myocardial I/R injury, mice were pretreated with SEV. The functional mechanism of miR-874 in I/R injury was explored when miR-874 and the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway were inhibited. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP biotin nick-end labeling (TUNEL) staining was used to detect cardiomyocyte apoptosis and dual luciferase reporter gene assay to identify the targeting relationship between miR-874 and STAT3. Expression of the JAK2/STAT3 signaling pathway and apoptosis-related genes was determined. Initially, upregulated miR-874 was observed in I/R mice. Then, miR-874 inhibition improved cardiac function of I/R mice, inhibited cardiomyocyte apoptosis (also shown as decreased Bcl-2 associated X protein B [Bax] and increased B-cell lymphoma-2 [Bcl-2]), and activated the JAK2/STAT3 signaling pathway. STAT3, a target gene of miR-874, was upregulated following miR-874 inhibition. Finally, we also observed that the effect of miR-874 was lost when the JAK2/STAT3 signaling pathway was blocked. The findings indicate miR-874 as a contributory role in cardiac I/R injury, with miR-874 inhibition alleviating cardiac I/R injury in mice following SEV pretreatment by targeting STAT3 through the JAK2/STAT3 signaling pathway.

Effects of sevoflurane preconditioning on microglia/macrophage dynamics and phagocytosis profile against cerebral ischemia in rats.

The effects of sevoflurane on microglia/macrophages, promoting or suppressing their activation, remains controversy. We aimed to determine whether sevoflurane preconditioning can protect brain via changing microglia/macrophage dynamics and phagocytosis profile after ischemia. The impact of sevoflurane preconditioning was evaluated on microglia/macrophage migration, phagocytosis and proliferation altogether from day 1 to day 7 after transient middle cerebral arterial occlusion (tMCAO) in rats. Sevoflurane preconditioning was identified to accelerate microglia/macrophage migrating to and invasion in the ischemic core from day 1 to day 5 after damage. Significant accumulation of amoeboid and phagocytic microglia/macrophages was observed in sevoflurane group from day 3 to day 5 after ischemia injury. In addition, sevoflurane pretreatment also promoted the proliferation of microglia/macrophage (Iba1+ /Ki67+ ) dramatically in ischemic core on day 3 postinsult. Our current study has identified the impact of sevoflurane preconditioning on microglia/macrophage dynamics, including its migration, phagocytosis, and proliferation at early stage after brain ischemia and reperfusion. Sevoflurane might enhance microglia/macrophage activation and promote brain repair. These results could help to approach more relevant microglia/macrophage cell-based strategy for human stroke therapy.

Effects of sevoflurane pretreatment on the apoptosis of rat H9c2 cardiomyocytes and the expression of GRP78.

The protective effect of sevoflurane on apoptosis of rat H9c2 cardiomyocytes induced by H2O2 and the effect on the expression of glucose-regulated protein 78 (GRP78) were investigated. H9c2 cells were routinely cultured and divided into the control, model and sevoflurane groups. Cells in the model group were treated with 400 µM H2O2, and cells in the sevoflurane group were pretreated with sevoflurane prior to treatment with 400 µM H2O2. MTT assay was used to assess cell viability. Annexin V-propidium iodide (AV-PI) double staining flow cytometry was used to detect apoptosis. The intracellular free Ca2+ concentration was measured by the fluorescence-based assay using Fluo-3 AM as a calcium ion fluorescence probe. The mRNA expression level of GRP78 and protein expression levels of GRP78, CHOP and caspase-12 were measured using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis, respectively. The assays showed that after sevoflurane pretreatment the H9c2 cell viability was significantly increased, whereas the H2O2-induced apoptosis, intracellular Ca2+ concentration, mRNA expression of GRP78, and the protein expression of GRP78, CHOP and caspase-12 were all reduced. The results show that pretreatment with sevoflurane inhibited H2O2-induced apoptosis in H9c2 cells. The mechanism may be related to inhibition of the stress-related protein GRP78 expression in endoplasmic reticulum, resulting in decreased intracellular Ca2+ concentration and the downregulation of CHOP and caspase-12 expression levels.

Effects of sevoflurane on NF-кB and TNF-α expression in renal ischemia-reperfusion diabetic rats.

Ischemia-reperfusion (I/R) injury is the main reason of acute renal failure. However, inflammatory response and cell apoptosis are important mechanisms implicated in I/R injury. Recent studies indicated that nuclear factor kappa B (NF-кB) and tumor necrosis factor α (TNF-α) are both involved in these mechanisms. Sevoflurane reduces NF-кB and TNF-α expression in rats' heart and decreases their renal I/R injury. However, few studies are available regarding the effect of sevoflurane on kidney of diabetic rats. Therefore, the aim of this study was to evaluate sevoflurane effect on NF-кB and TNF-α expression in diabetic rats to decrease renal I/R injury. Male Sprague-Dawley rats were divided into five groups: Group A, non-diabetic rats underwent sham operation; Group B, non-diabetic rats with renal I/R injury; Group C, diabetic rats underwent sham operation; Group D, diabetic rats with renal I/R injury; Group E, diabetic rats with renal I/R injury after sevoflurane pretreatment. Rats of Group E were exposed to 2.5% sevoflurane for 30min. After 24h, creatinine (Cr), blood urea nitrogen (BUN), renal cell apoptosis, and NF-кB and TNF-α expression in kidney were assessed. Renal cell apoptosis, NF-кB, and TNF-α expression were significantly higher in diabetic rats with renal I/R injury group compared to diabetic rats that underwent sham operation (P<0.01). These changes were significantly reduced by sevoflurane (P<0.01). Sevoflurane exerted a protective effect against renal injury by lowering the expression of NF-кB and TNF-α in renal I/R diabetic rats.

Sevoflurane suppresses microglial M2 polarization.

Microglia can be polarized into the classical (M1) or alternative (M2) activation states in response to various stimuli. The M2 phenotype has its own set of receptor profiles, cytokine production, and chemokine secretion, of which arginase 1 (Arg1), chitinase 3-like 3 (Chi3l3, Ym1), and IL-10 have neuroprotective properties. Sevoflurane is one of the most commonly used volatile anesthetics in clinics. Previous studies have shown that sevoflurane promotes microglial M1 activation. However, it remains unclear whether sevoflurane regulates microglial M2 activation. In this study, we found that sevoflurane treatment abolished interleukin 4 (IL-4)-induced M2 microglial activation. Our results indicate that IL-4-mediated induction of the characteristic M2 marker genes and proteins Arg1, Ym1, and IL-10 was significantly attenuated by sevoflurane pretreatment in primary microglia. Microglial M2 polarization induced by incubation with culture supernatant from human umbilical cord mesenchymal stromal cells (HUC-MSCs) was abolished by treatment with 2% or 4% sevoflurane. Upregulation of SOCS1 and suppression of SOCS3 were shown to play a crucial role in the process of M2 microglial polarization. Our results also indicate that SOCS1 expression was induced by IL-4, but it was inhibited by pretreatment with sevoflurane. In contrast, IL-4 suppressed SOCS3 expression, which was restored by pretreatment with sevoflurane. Mechanistically, it was shown that sevoflurane suppresses STAT6 phosphorylation in primary microglia.

Sevoflurane pretreatment inhibits the myocardial apoptosis caused by hypoxia reoxygenation through AMPK pathway: An experimental study.

To study whether sevoflurane pretreatment inhibits the myocardial apoptosis caused by hypoxia reoxygenation through AMPK pathway. H9c2 myocardial cell lines were cultured and divided into control group (C group), hypoxia reoxygenation group (H/R group), sevoflurane pretreatment+hypoxia reoxygenation group (SP group) and sevoflurane combined with Compound C pretreatment+hypoxia reoxygenation group (ComC group), and the cell proliferation activity and apoptosis rate, myocardial enzyme levels in culture medium as well as the expression of apoptosis genes and p-AMPK in cells were determined. p-AMPK expression in cells of H/R group was significantly lower than that of C group, SP group was significantly higher than that of H/R group; cell proliferation activity value and Bcl-2 expression in cells of H/R group were significantly lower than those of C group, SP group were significantly higher than those of H/R group, ComC group were significantly lower than those of SP group; apoptosis rate, LDH, CK and AST levels as well as the Bax and Caspase-3 expression in cells of H/R group were significantly higher than those of C group, SP group were significantly lower than those of H/R group, ComC group were significantly higher than those of SP group. Sevoflurane pretreatment can activate AMPK signaling pathway to inhibit the myocardial apoptosis caused by hypoxia reoxygenation.

Effects of TLR3 and TLR9 Signaling Pathway on Brain Protection in Rats Undergoing Sevoflurane Pretreatment during Cardiopulmonary Bypass.

Objective To investigate the effects of TLR3 and TLR9 signaling pathway on brain injury during CPB in rats pretreated with sevoflurane and its possible molecular mechanism. Methods SD rats were randomly assigned to sham group, CPB group, and Sev group. Brain tissue was obtained at before CPB (T0), at CPB for 30 minutes (T1), 1 hour after CPB (T3), and 3 hours after CPB (T5). ELISA was used to measure S100-β and IL-6. Western blot was utilized to determine TLR3 and TLR9 expression. TUNEL was applied to detect neuronal apoptosis. Results Compared with CPB group, at T1, at termination after 1 hour of CPB (T2), T3, 2 hours after CPB (T4) and T5, S100-β and IL-6 decreased in Sev group. Compared with CPB group, IFN-β were increased in Sev group, except T0. Compared with CPB group, TLR3 expression increased, and TLR9 and NF-κB decreased in Sev group. The apoptotic neurons were less in Sev group than in CPB group (P < 0.05). Conclusion Sevoflurane intervention can activate TLR3 and TLR9 signaling pathway, upregulate TLR3 expression and downstream TRIF expression, decrease TLR9 expression, and downregulate downstream NF-κB expression in CPB rat models, thereby mitigating brain injury induced by inflammatory response during CPB.