• Anesthesia
• Hepatectomy
• Inhalational anesthesia
• Liver transplant
• Propofol

• Humans
• Liver Transplantation/methods
• Hepatectomy/methods
• Propofol/administration & dosage
• Anesthesia, Intravenous/methods
• Anesthetics, Intravenous/administration & dosage
• Randomized Controlled Trials as Topic
• Anesthesia, Inhalation/methods
• Anesthetics, Inhalation/administration & dosage
• Observational Studies as Topic

• Acute respiratory distress syndrome
• Apoptosis
• Autophagy
• Sevoflurane
• Wound healing

• Sevoflurane/pharmacology
• Humans
• Respiratory Distress Syndrome/drug therapy
• Respiratory Distress Syndrome/pathology
• Wound Healing/drug effects
• Cell Survival/drug effects
• A549 Cells
• Cell Proliferation/drug effects
• Alveolar Epithelial Cells/drug effects
• Alveolar Epithelial Cells/metabolism
• Alveolar Epithelial Cells/pathology
• Cell Movement/drug effects
• Anesthetics, Inhalation/pharmacology
• Cytokines/metabolism
• Autophagy/drug effects
• Pulmonary Alveoli/drug effects
• Pulmonary Alveoli/pathology

• Anesthesia
• Initial poor graft function
• Ischemia-reperfusion injury
• Living donor liver transplantation
• Sevoflurane

• Fonds de Recherche Clinique research grant from Cliniques Universitaires Saint-Luc, Brussels.

• colorectal cancer
• liver metastasis
• ischemia-reperfusion injury
• sevoflurane preconditioning

• Humans
• Sevoflurane/pharmacology
• Prospective Studies
• Anesthetics, Inhalation/therapeutic use
• Anesthetics, Inhalation/pharmacology
• Ischemic Preconditioning/methods
• Ischemia/drug therapy
• Ischemia/prevention & control
• Reperfusion
• Lactates

• 0121U110087 Ministry of Health of Ukraine

• Anesthesia
• Cognitive dysfunction
• Gut dysbiosis
• Gut microbiota
• Neuroinflammation
• Perioperative cognitive dysfunction
• Perioperative delirium

• Akt
• Bcl-xL
• IPS
• ROS
• anesthetic preconditioning
• cell death
• metformin
• myocardial ischemic
• reperfusion

Numerous tissue-derived factors have been postulated to be involved in tissue migration of circulating monocytes. The aim of this study was to evaluate whether a defined hypoxic gradient can induce directed migration of naïve human monocytes and to identify responsible autocrine/paracrine factors.

Monocytes were isolated from peripheral blood mononuclear cells, transferred into chemotaxis chambers and subjected to a defined oxygen gradient with or without the addition of CCL26. Cell migration was recorded and secretome analyses were performed.

Cell migration recordings revealed directed migration of monocytes towards the source of hypoxia. Analysis of the monocyte secretome demonstrated a reduced secretion of 70% (19/27) of the analyzed cytokines under hypoxic conditions. The most down-regulated factors were CCL26 (− 99%), CCL1 (− 95%), CX3CL1 (− 95%), CCL17 (− 85%) and XCL1 (− 83%). Administration of recombinant CCL26 abolished the hypoxia-induced directed migration of human monocytes, while the addition of CCL26 under normoxic conditions resulted in a repulsion of monocytes from the source of CCL26.

Hypoxia induces directed migration of human monocytes in-vitro. Autocrine/paracrine released CCL26 is involved in the hypoxia-mediated monocyte migration and may represent a target molecule for the modulation of monocyte migration in-vivo.

• CCL26
• Cytokines
• Hypoxia
• Migration
• Monocytes

• cytokines
• ischaemia/reperfusion injury
• monocytes
• neoangiogenesis
• remodelling
• wound healing

• Cell Differentiation/physiology
• Cell Movement/physiology
• Cells, Cultured
• Cytokines/metabolism
• Endothelial Cells/metabolism
• Endothelial Cells/pathology
• Humans
• Monocytes/metabolism
• Monocytes/pathology
• Neovascularization, Pathologic/metabolism
• Neovascularization, Pathologic/pathology
• Reperfusion Injury/metabolism
• Reperfusion Injury/pathology
• Wound Healing/physiology

• F359921 Schleswig-Holstein's Ministry of Science, Economy and Transport

• Cerebral ischemia/reperfusion injury
• Oxygen-glucose deprivation and reoxygenation
• Sevoflurane
• XIAP
• miR-181a

Hypoxic-ischemic brain injury in the perinatal period is a main cause of perinatal mortality and neurologic complications in neonates and children. Recent studies have focused on the neuroprotective effect of anesthetic drugs. The volatile anesthetic isoflurane has been shown to exert neuroprotective effects in cerebral ischemia. Mangiferin is a natural polyphenol with various pharmacological properties, including antioxidant and ant-tumor effects. This study aimed to determine whether mangiferin potentiates the neuroprotective effects of isoflurane and also if mangiferin when administered alone exerts neuroprotective effects following hypoxic-ischemic brain injury.

Sprague-Dawley rats were subjected to cerebral hypoxic ischemia on postnatal day 10 (P10). Mangiferin (50, 100, or 200 mg/kg b.w.) was intragastrically administered from P3 to P12 and 1 h prior to insult on the day of ischemic induction. At 3 h after hypoxia-ischemia (HI) insult, separate groups of rat pups were exposed to isoflurane (1.5%) for 6 h. Following 48 h of HI, the rats were sacrificed and brain tissues were used for analysis.

Mangiferin treatment attenuated neuronal apoptosis and reduced cerebral infarct volume. The expression of cleaved caspase-3 and apoptotic cascade proteins were regulated. The levels of reactive oxygen species (ROS) and malondialdehyde were reduced by mangiferin and/or isoflurane exposure. The levels of antioxidant glutathione were considerably raised under HI injury, which was modulated by mangiferin and isoflurane exposure. The PI3K/Akt signaling pathway, which was downregulated following HI insult, was activated by mangiferin and/or isoflurane.

This study reveals the potent neuroprotective efficacy of mangiferin against HI-induced brain injury via effectively modulating apoptotic pathways, ROS levels, and PI3K/Akt cascades while potentiating protective effects of isoflurane.

The family of vascular endothelial growth factors (VEGFs) are known for their regulation of vascularization. In the brain, VEGFs are important regulators of angiogenesis, neuroprotection and neurogenesis. Dysregulation of VEGFs is involved in a large number of neurodegenerative diseases and acute neurological insults, including stroke. Stroke is the main cause of acquired disabilities, and normally results from an occlusion of a cerebral artery or a hemorrhage, both leading to focal ischemia. Neurons in the ischemic core rapidly undergo necrosis. Cells in the penumbra are exposed to ischemia, but may be rescued if adequate perfusion is restored in time. The neuroprotective and angiogenic effects of VEGFs would theoretically make VEGFs ideal candidates for drug therapy in stroke. However, contradictory to what one might expect, endogenously upregulated levels of VEGF as well as the administration of exogenous VEGF is detrimental in acute stroke. This is probably due to VEGF-mediated blood–brain-barrier breakdown and vascular leakage, leading to edema and increased intracranial pressure as well as neuroinflammation. The key to understanding this Janus face of VEGF function in stroke may lie in the timing; the harmful effect of VEGFs on vessel integrity is transient, as both VEGF preconditioning and increased VEGF after the acute phase has a neuroprotective effect. The present review discusses the multifaceted action of VEGFs in stroke prevention and therapy.

• VEGF
• exercise
• growth factor
• ischemia
• stroke

• Blood-Brain Barrier/drug effects
• Blood-Brain Barrier/pathology
• Brain Ischemia/drug therapy
• Brain Ischemia/genetics
• Brain Ischemia/pathology
• Humans
• Neovascularization, Pathologic/drug therapy
• Neovascularization, Pathologic/genetics
• Neovascularization, Pathologic/pathology
• Neurons/metabolism
• Neuroprotective Agents/therapeutic use
• Stroke/drug therapy
• Stroke/genetics
• Stroke/pathology
• Vascular Endothelial Growth Factor A/genetics

• 2-iminobiotin
• apoptosis
• asphyxia
• cell damage
• hypothermia
• hypoxia-ischemia
• in vitro
• neuroprotection

• Cell protection
• Doxycycline
• Hypoxia
• Intestinal cells
• Intestinal ischemia
• Ischemia/reperfusion injury

• 2-iminobiotin
• Asphyxia
• Brain
• Cell damage
• Hypoxia-ischemia
• In-vitro
• Neuroprotection

• anesthetic/technique
• cancer recurrence
• organ failure
• outcome
• postoperative cognitive dysfunction
• stress

Different anesthesia regimes are commonly used in experimental models of cardiac arrest, but the effects of various anesthetics on clinical outcome parameters are unknown. We conducted a study in which we subjected rats to cardiac arrest under medetomidine/ketamine or sevoflurane/fentanyl anesthesia.

Asystolic cardiac arrest for 8 minutes was induced in 73 rats with a mixture of potassium chloride and esmolol. Daily behavioral and neurological examination included the open field test (OFT), the tape removal test (TRT) and a neurodeficit score (NDS). Animals were randomized for sacrifice on day 2 or day 5 and brains were harvested for histology in the hippocampus cornus ammonis segment CA1. The inflammatory markers IL-6, TNF-α, MCP-1 and MIP-1α were assessed in cerebrospinal fluid (CSF). Proportions of survival were tested with the Fisher’s exact test, repeated measurements were assessed with the Friedman’s test; the baseline values were tested using Mann–Whitney U test and the difference of results of repeated measures were compared.

In 31 animals that survived beyond 24 hours neither OFT, TRT nor NDS differed between the groups; histology was similar on day 2. On day 5, significantly more apoptosis in the CA1 segment of the hippocampus was found in the sevoflurane/fentanyl group. MCP-1 was higher on day 5 in the sevoflurane/fentanyl group (p = 0.04). All other cyto- and chemokines were below detection threshold.

In our cardiac arrest model neurological function was not influenced by different anesthetic regimes; in contrast, anesthesia with sevoflurane/fentanyl results in increased CSF inflammation and histologic damage at day 5 post cardiac arrest.

Increases in plasma kynurenic acid (KYNA) concentration relate to the severity of inflammation. The aim of this study was to analyse changes in plasma KYNA concentration and neutrophil/lymphocyte ratio (NLR) in cardiac surgery patients. Additionally, the effect of anaesthesia was analysed. Adult cardiac surgery patients under intravenous general anaesthesia were studied. Additionally, some patients received sevoflurane (SEV) prior to cardiopulmonary bypass. Plasma KYNA concentration and NLR were measured before anaesthesia, just after surgery and on postoperative days 1, 2 and 3. Patients were assigned to two groups: patients who did not receive SEV (NonSEV group) and patients who received SEV (SEV group). Forty-three patients were studied. Twenty-four of them received SEV. KYNA increased immediately after surgery and remained elevated through postoperative day 3 in the NonSEV group, whereas it was similar to the preoperative concentration in the SEV group. NLR increased immediately after surgery in both groups, and higher values were noted in the NonSEV group than in the SEV group at postoperative days 2 and 3. Plasma KYNA concentration correlated with NLR in the NonSEV group. Cardiac surgery caused an increase in NLR. Plasma KYNA increased in the NonSEV group and correlated with NLR. Administration of SEV inhibited the increase in KYNA, most likely due to its anti-inflammatory properties.

Cancer is the second most common cause of death in the United States. Metastatic disease is a more important cause of cancer-related death relative to primary tumor progression. Surgical excision is the primary treatment for most malignant tumors. However, surgery itself can inhibit important host defenses and promote the development of metastases. An altered balance between the metastatic potential of the tumor and the anti-metastatic host defenses, including cell-mediated immunity and natural killer cell function, is a plausible mechanism of increased cancer metastasis. This article reviews the increasingly recognized concept of anesthetic technique along with perioperative factors and their potential to affect long-term outcome after cancer surgery. The potential effect of intravenous anesthetics, volatile agents, local anesthetic drugs, opiates, and non-steroidal anti-inflammatory drugs are reviewed along with recent literature and ongoing clinical trials in this area. Regional anesthesia is increasingly emerging as a safer option with less cancer recurrence potential as compared to general anesthesia. Blood transfusion, pain, stress, use of beta-blockers, and hypothermia are other potentially important perioperative factors to consider.

• Cancer
• Recurrence
• Survival
• Anesthesia
• Perioperative
• Factors

Bone marrow mesenchymal stem cells (MSCs) have been found to produce beneficial effects on ischemia-reperfusion injury. However, most of the MSCs died when transplanted into the ischemic tissue, which severely limit their therapeutic potential.

Using an in vitro model of hypoxia and serum deprivation (H/SD), we investigated the hypothesis that sevoflurane preconditioning could protect MSCs against H/SD-induced apoptosis and improve their migration, proliferation, and therapeutic potential. The H/SD of MSCs and neuron-like PC12 cells were incubated in a serum-free medium and an oxygen concentration below 0.1% for 24 h. Sevoflurane preconditioning was performed through a 2-h incubation of MSCs in an airtight chamber filled with 2 vol% sevoflurane. Apoptosis of MSCs or neuron-like PC12 cells was assessed using Annexin V-FITC/propidium iodide (PI). Furthermore, the mitochondrial membrane potential was assessed using lipophilic cationic probe. The proliferation rate was evaluated through cell cycle analysis. Finally, HIF-1α, HIF-2α, VEGF and p-Akt/Akt levels were measured by western blot.

Sevoflurane preconditioning minimized the MSCs apoptosis and loss of mitochondrial membrane potential. Furthermore, it increased the migration and expression of HIF-1α, HIF-2α, VEGF, and p-Akt/Akt, reduced by H/SD. In addition, neuron-like PC12 cells were more resistant to H/SD-induced apoptosis when they were co-cultured with sevoflurane preconditioning MSCs.

These findings suggest that sevoflurane preconditioning produces protective effects on survival and migration of MSCs against H/SD, as well as improving the therapeutic potential of MSCs. These beneficial effects might be mediated at least in part by upregulating HIF-1α, HIF-2α, VEGF, and p-Akt/Akt.

• Animals
• Apoptosis/drug effects
• Biomarkers/metabolism
• Cell Hypoxia/drug effects
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Cell Survival/drug effects
• Culture Media, Serum-Free/pharmacology
• Flow Cytometry
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/drug effects
• Mesenchymal Stem Cells/enzymology
• Methyl Ethers/pharmacology
• PC12 Cells
• Proto-Oncogene Proteins c-akt/metabolism
• Rats
• Rats, Sprague-Dawley
• Sevoflurane

• Endothelial cells
• Hypoxia
• Intestinal ischemia
• Ischemia/reperfusion injury
• Remote ischemic preconditioning

Ischemia-reperfusion injury and tissue hypoxia are of high clinical relevance because they are associated with various pathophysiological conditions such as myocardial infarction and stroke. Nevertheless, the underlying mechanisms causing cell damage are still not fully understood, which is at least partially due to the lack of cell culture systems for the induction of rapid and transient hypoxic conditions. The aim of the study was to establish a model that is suitable for the investigation of cellular and molecular effects associated with transient and long-term hypoxia and to gain insights into hypoxia-mediated mechanisms employing a neuronal culture system. A semipermeable membrane insert system in combination with the hypoxia-inducing enzymes glucose oxidase and catalase was employed to rapidly and reversibly generate hypoxic conditions in the culture medium. Hydrogen peroxide assays, glucose measurements and western blotting were performed to validate the system and to evaluate the effects of the generated hypoxia on neuronal IMR-32 cells. Using the insert-based two-enzyme model, hypoxic conditions were rapidly induced in the culture medium. Glucose concentrations gradually decreased, whereas levels of hydrogen peroxide were not altered. Moreover, a rapid and reversible (onoff) generation of hypoxia could be performed by the addition and subsequent removal of the enzyme-containing inserts. Employing neuronal IMR-32 cells, we showed that 3 hours of hypoxia led to morphological signs of cellular damage and significantly increased levels of lactate dehydrogenase (a biochemical marker of cell damage). Hypoxic conditions also increased the amounts of cellular procaspase-3 and catalase as well as phosphorylation of the pro-survival kinase Akt, but not Erk1/2 or STAT5. In summary, we present a novel framework for investigating hypoxia-mediated mechanisms at the cellular level. We claim that the model, the first of its kind, enables researchers to rapidly and reversibly induce hypoxic conditions in vitro without unwanted interference of the hypoxia-inducing agent on the cultured cells. The system could help to further unravel hypoxia-associated mechanisms that are clinically relevant in various tissues and organs.

Sevoflurane is an anesthetic agent which also participates in protective mechanisms in sepsis, likely due to anti-inflammatory properties. A key tissue in sepsis is the endothelium, which expresses TLR2 and TLR4 receptors, known regulators of inflammatory mechanisms and potential therapeutic targets for this pathology. In this context, we explored the effect of sevoflurane postconditioning in an in vitro sepsis model.

Primary cultures of human umbilical vein endothelial cells were used for two different experiments. In the first set, cultures were placed in an airtight incubation chamber and exposed to different concentrations of sevoflurane (0,1,3 or 7% vol,) for 1 hour. In the second set, lipopolysaccharide from Escherichia coli 0111:B4 (1 μg/mL) was added to culture medium for 3 hours and cells were subsequently exposed to sevoflurane (0,1,3 or 7% vol,) for 1 hour as explained before. In both cases, cell viability was measured by MTT and Trypan blue assays, TLR2 and TLR4 expression were analyzed by flow cytometry, and TNFα and IL-6 levels were quantified in cell culture media by an immunoassay immediately after exposure, at 6 and 24 hours.

Exposure to 3% sevoflurane decreased TLR2 at 24 hours and TLR4 at 6 and 24 hours (both p<0.05), whereas exposure to 7% decreased TLR4 expression at 6 hours (p<0.05). Both 3 and 7% sevoflurane decreased TNF-α and IL-6 levels at 24 hours (both p<0.05). In LPS-stimulated cultures, exposure to 3% sevoflurane was cytoprotective at 6 and 24 hours (p<0.05) compared with control, and decreased TLR2 and TLR4 expression at 24 hours (p<0.05); whereas 7% decreased TLR4 expression at 24 hours (p<0.05). Both 3% and 7% sevoflurane decreased TNF-α and IL-6 levels at 24 hours (both p<0.05).

Postconditioning with the halogenated anesthetic agent sevoflurane after LPS stimulation shows a cytoprotective effect in an in vitro model, decreasing cell death and reducing TLR2 and TLR4 expression as well as levels of the inflammatory mediators TNF-α and IL-6 in human endothelial cells.

Oxygen deficiency in tumor tissue is associated with a malign phenotype, characterized by high invasiveness, increased metastatic potential and poor prognosis. Hypoxia chambers are the established standard model for in vitro studies on tumor hypoxia. An enzymatic hypoxia system (GOX/CAT) based on the use of glucose oxidase (GOX) and catalase (CAT) that allows induction of stable hypoxia for in vitro approaches more rapidly and with less operating expense has been introduced recently. Aim of this work is to compare the enzymatic system with the established technique of hypoxia chamber in respect of gene expression, glucose metabolism and radioresistance, prior to its application for in vitro investigation of oxygen deficiency.

Human head and neck squamous cell carcinoma HNO97 cells were incubated under normoxic and hypoxic conditions using both hypoxia chamber and the enzymatic model. Gene expression was investigated using Agilent microarray chips and real time PCR analysis. ¹⁴C-fluoro-deoxy-glucose uptake experiments were performed in order to evaluate cellular metabolism. Cell proliferation after photon irradiation was investigated for evaluation of radioresistance under normoxia and hypoxia using both a hypoxia chamber and the enzymatic system.

The microarray analysis revealed a similar trend in the expression of known HIF-1 target genes between the two hypoxia systems for HNO97 cells. Quantitative RT-PCR demonstrated different kinetic patterns in the expression of carbonic anhydrase IX and lysyl oxidase, which might be due to the faster induction of hypoxia by the enzymatic system. ¹⁴C-fluoro-deoxy-glucose uptake assays showed a higher glucose metabolism under hypoxic conditions, especially for the enzymatic system. Proliferation experiments after photon irradiation revealed increased survival rates for the enzymatic model compared to hypoxia chamber and normoxia, indicating enhanced resistance to irradiation. While the GOX/CAT system allows independent investigation of hypoxia and oxidative stress, care must be taken to prevent acidification during longer incubation.

The results of our study indicate that the enzymatic model can find application for in vitro investigation of tumor hypoxia, despite limitations that need to be considered in the experimental design.