Propofol improves survival in a murine model of sepsis via inhibiting Rab5a-mediated intracellular trafficking of TLR4.

BACKGROUND: Propofol is a widely used anesthetic and sedative, which has been reported to exert an anti-inflammatory effect. TLR4 plays a critical role in coordinating the immuno-inflammatory response during sepsis. Whether propofol can act as an immunomodulator through regulating TLR4 is still unclear. Given its potential as a sepsis therapy, we investigated the mechanisms underlying the immunomodulatory activity of propofol. METHODS: The effects of propofol on TLR4 and Rab5a (a master regulator involved in intracellular trafficking of immune factors) were investigated in macrophage (from Rab5a-/- and WT mice) following treatment with lipopolysaccharide (LPS) or cecal ligation and puncture (CLP) in vitro and in vivo, and peripheral blood monocyte from sepsis patients and healthy volunteers. RESULTS: We showed that propofol reduced membrane TLR4 expression on macrophages in vitro and in vivo. Rab5a participated in TLR4 intracellular trafficking and both Rab5a expression and the interaction between Rab5a and TLR4 were inhibited by propofol. We also showed Rab5a upregulation in peripheral blood monocytes of septic patients, accompanied by increased TLR4 expression on the cell surface. Propofol downregulated the expression of Rab5a and TLR4 in these cells. CONCLUSIONS: We demonstrated that Rab5a regulates intracellular trafficking of TLR4 and that propofol reduces membrane TLR4 expression on macrophages by targeting Rab5a. Our study not only reveals a novel mechanism for the immunomodulatory effect of propofol but also indicates that Rab5a may be a potential therapeutic target against sepsis.

Medium- and long-chain triglyceride propofol activates PI3K/AKT pathway and inhibits non-alcoholic fatty liver disease by inhibiting lipid accumulation.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease. The mechanism by which medium- and long-chain triglyceride (MCT/LCT) propofol plays a role in promoting NAFLD remains unclear. In this study, we investigated the effect of MCT/LCT propofol on NAFLD progression and its mechanism of action. In Huh-7 and HepG3 cells induced by free fatty acids (FFA), propofol downregulated the expression levels of TG and lipid metabolism-related proteins by promoting the activation of the PI3K/AKT pathway and suppressing FFA-induced lipid metabolic disorders. In a high-fat diet (HFD) -induced NAFLD mouse model, we demonstrated that propofol significantly inhibited liver steatosis, inflammatory cell infiltration, and fibrosis. In conclusion, our results suggest that MCT/LCT propofol reduces liver lipid accumulation by activating the PI3K/AKT pathway and further suppressing the NAFLD process.

Propofol Promoted the Cell Growth and Epithelial Mesenchymal Transformation of the HTR-8/SVneo Cells through Targeting the METTL3 Mediated ZEB2.

Preeclampsia (PE) belongs to hypertensive disorder complicating pregnancy, which is a serious obstetric complication. Propofol is a new type of fast and short-acting general anesthetic, which has also been demonstrated to promote the cell growth recently. Therefore, this study was carried out to explore the effects of propofol on the cell growth, migration and invasion in the HTR-8/SVneo cells. The cell biological behaviors were analyzed using CCK-8, EdU, transwell assays. The relationship between METTL3 and ZEB2 was confirmed by RIP assay. Western blot and RT-qPCR assays were carried out to detect the protein and mRNA levels. The results showed that propofol enhanced the cell viability, proliferation, migration and invasion of the HTR-8/SVneo cells. Besides, METTL3 overexpression neutralized the propofol role. Furthermore, METTL3 overexpression elevated the m6A levels of ZEB2 and decreased the mRNA levels and stability of ZEB2. ZEB2 overexpression neutralized the role of METTL3 in the propofol treated HTR-8/SVneo cells. In conclusion, this study demonstrated the effects of propofol on promoting the cell growth, migration and invasion of HTR-8/SVneo cells. Mechanistically, propofol indirectly regulated ZEB2 expression by targeting METTL3 mediated m6A methylation modification.

Simple quantification of propofol and its metabolites in blood and urine using gas chromatography-tandem mass spectrometry (GC-MS/MS).

An analytical method which was used for the simultaneous detection and quantification of propofol and its metabolites in human blood and urine by gas chromatography-tandem mass spectrometry (GC-MS/MS) was newly established and applied to authentic human samples obtained from the deceased. The QuEChERS method was employed, and then analyzed by GC-MS/MS. We separately used sulfatase and ß-glucuronidase to hydrolyze the urine sample and calculated the increase of propofol and 4-hydroxypropofol before and after the hydrolysis. The results of urinary concentrations in urine from the subject were: 4.88 µg/mL for propofol, 0.53 µg/mL for 4-hydroxypropofol, 3.35 µg/mL for propofol-glucuronide, 0.31 µg/mL for the total concentration of 1-(2,6-diisopropyl-1,4-quinol)-glucuronide plus 4-(2,6-diisopropyl-1,4-quinol)-glucuronide, and 0.39 µg/mL for 4-(2,6- diisopropyl-1,4-quinol)-sulfate. The lower limit of quantification was 10 ng/mL for all determined compounds; the extraction recoveries were not less than 57.2 %. Intraday and interday precisions and accuracies were all less than 10 %. The calibration curves for propofol and 4-hydroxypropofol in human urine showed the correlation values of not less than 0.999; propofol and 4-hydroxypropofol in blood also presented good linearities in the concentration ranges of 0.1-10 µg/mL. The two compounds had good stability within 7 days at 25, 4, and -20 ℃. To our knowledge, this is the first trial to establish a simple and reliable method to simultaneously detect and quantify of propofol and its phase I and II metabolites in human blood and urine samples by GC-MS/MS.

Dexmedetomidine alleviates propofol-induced neural injury in developing rats.

Propofol, a commonly used intravenous anesthetic, has been associated with neurodegeneration in the developing brain upon repeated exposure. Dexmedetomidine is an α2 adrenoceptor agonist that was previously reported to possess neuroprotective properties. Here, we confirmed the impacts of dexmedetomidine on propofol-induced neuroapoptosis and subsequent spatial learning and memory deficits in neonatal rats. We found that dexmedetomidine effectively mitigated propofol-induced spatial learning and memory impairments and improved aversive memory in developing rats. Dexmedetomidine reduced propofol-induced cell apoptosis in the hippocampus and modulated the mRNA expression of Bcl-2 and Bax. Additionally, dexmedetomidine attenuated the propofol-induced increase of inflammatory factors IL-6 and TNF-α. The reduced phosphorylation levels of Akt and CREB levels by propofol were re-activated by dexmedetomidine. In conclusion, our findings demonstrated that dexmedetomidine effectively mitigated propofol-induced cognitive and memory impairments in developing rats by modulating apoptosis and reducing inflammation via activating the Akt/CREB/BDNF signaling pathway. These findings suggest potential strategies to protect the developing brain from the adverse effects of anesthetics and improve patient care in pediatric anesthesia practice.

Propofol exerts anti-anhedonia effects via inhibiting the dopamine transporter.

Lasker's award-winning drug propofol is widely used in general anesthesia. The recreational use of propofol is reported to produce a well-rested feeling and euphoric state; yet, the neural mechanisms underlying such pleasant effects remain unelucidated. Here, we report that propofol actively and directly binds to the dopamine transporter (DAT), but not the serotonin transporter (SERT), which contributes to the rapid relief of anhedonia. Then, we predict the binding mode of propofol by molecular docking and mutation of critical binding residues on the DAT. Fiber photometry recording on awake freely moving mice and [18F] FP-CIT-PET scanning further establishes that propofol administration evokes rapid and lasting dopamine accumulation in nucleus accumbens (NAc). The enhanced dopaminergic tone drives biased activation of dopamine-receptor-1-expressing medium spiny neurons (D1-MSNs) in NAc and reverses anhedonia in chronically stressed animals. Collectively, these findings suggest the therapeutic potential of propofol against anhedonia, which warrants future clinical investigations.

Dexmedetomidine attenuates postoperative spatial memory impairment after surgery by reducing cytochrome C.

BACKGROUND: Anesthesia and surgery can induce perioperative neurocognitive disorders (PND). Mitochondrial dysfunction has been proposed to be one of the earliest triggering events in surgery-induced neuronal damage. Dexmedetomidine has been demonstrated to attenuate the impairment of cognition in aged rats induced by surgery in our previous study. METHODS: Male Sprague-Dawley rats underwent hepatic apex resection under anesthesia with propofol to clinically mimic human abdominal surgery. The rats were divided into three groups: Control group, Model group and Dexmedetomidine (Dex) group. Cognitive function was evaluated with the Morris water maze (MWM), Open Field Test (OFT)and Novel object recognition task (NOR). Ultrastructural change in neuronal mitochondria was measured by transmission electron microscopy. Mitochondrial function was measured by mitochondrial membrane potential and activities of mitochondrial complexes. Neuronal morphology was observed with H&E staining and the activation of glial cells was observed by immunohistochemistry in the hippocampus. Protein levels were measured by Western blot (WB) and immunofluorescence at 3 and 7 days after surgery. RESULTS: Surgery-induced cognitive decline lasts three days, but not seven days after surgery in the model group. Transmission electron microscope showed the mitochondrial structure damage in the model group, similar changes were not induced in the Dex group. Dexmedetomidine may reverse the decrease in mitochondrial membrane potential and mitochondrial complex activity. Compared with the Control group, the expression of cytochrome c was significantly increased in model group by Western blot and immunofluorescence on days 3, but not day 7. Rats from the Model group expressed significantly greater levels of Iba-1 and GFAP compared with the Control group and the Dex group. CONCLUSION: Dexmedetomidine appears to reverse surgery-induced behavior, mitigate the higher density of Iba-1 and GFAP, reduce the damage of mitochondrial structure and function by alleviating oxidative stress and protect mitochondrial respiratory chain, thus increasing cytochrome c oxidase (COX) expression and downregulate the expression of cytochrome c protein in the hippocampus of rats.

Propofol mediates bone metastasis by regulating PC-derived exosomal miR-142-3p.

In this study we investigated the role of propofol in mediating prostate cancer (PCa) bone metastasis through regulating exosomal factors derived from PCa. We isolated exosomes from PCa cells and co-cultured them with mesenchymal stem cells (MSCs). PCa-derived exosomes increased calcium deposition of MSCs and upregulated ALPL'Alkaline phosphatase, tissue-nonspecific isozyme) and BGLAP (Bone Gamma-Carboxyglutamate Protein) expression. Propofol treatment reduced alkaline phosphatase (ALP) activity, and ALPL and BGLAP expression that was induced by PCa-derived exosomes in MSCs. miRNAs present in cancer cell-derived exosomes increased osteogenesis in these cells. We evaluated miRNA expression in PCa cells after treatment with propofol, and found that miR-142-3p was upregulated in PCa cells. Furthermore, we transfected MSCs with miR-142-3p mimics or inhibitors and revealed that miR-142-3p mimics reduced calcium deposition and downregulated ALP activity, and ALPL and BGLAP levels, while miR-142-3p inhibitors increased calcium deposition and increased ALP activity, and ALPL and BGLAP levels. Finally, we determined that MSCs co-cultured with PCa-derived exosomes and transfected with miR-142-3p mimic exhibited reduced calcium deposition and lower ALP activity, and expression of ALPL and BGLAP. These data demonstrate that propofol inhibits osteogenic differentiation and mineralization of MSCs induced by PCa-derived exosomes by regulation of miR-142-3p levels.

Ecological risk assessment of environmentally relevant concentrations of propofol on zebrafish (Danio rerio) at early life stage: Insight into physiological, biochemical, and molecular aspects.

Propofol is an intravenous anesthetic injection extensively used in clinic, which has been proved to be neurotoxic in humans. Improper use and disposal of propofol may lead to its release into the aquatic environment, but the potential ecological risk of propofol to aquatic organisms remains poorly understood. For this study, we comprehensively explored the ecotoxicological effects and potential mechanisms of propofol (0.04, 0.2 and 2 mg L-1) on 120 hpf zebrafish (Danio rerio) embryos from physiological, biochemical, and molecular perspectives. The results showed that propofol has moderate toxicity on zebrafish embryos (96 h LC50 = 4.260 mg L-1), which could significantly reduce the hatchability and delay the development. Propofol can trigger reactive oxygen species (ROS) generation, lipid peroxidation (Malondialdehyde, MDA) and DNA damage (8-hydroxy-2-deoxyguanosine, 8-OHdG). The glutathione peroxidase (GPX) activity of zebrafish embryos in 0.04 and 0.2 mg L-1 propofol treatment group was activated in response to oxidative damage, while activities of superoxide dismutase (SOD), catalase (CAT) and GPX in zebrafish treated with 2 mg L-1 was significant inhibited compared with the control group (p＜0.05). Moreover, the expression of antioxidant genes and related pathways was inhibited. Apoptosis was investigated at genes level and histochemistry. Molecular docking confirmed that propofol could change in the secondary structure of acetylcholinesterase (AChE) and competitively inhibited acetylcholine (ACh) binding to AChE, which may disturb the nervous system. These results described toxic response and molecular mechanism in zebrafish embryos, providing multiple aspects about ecological risk assessment of propofol in water environment.

Evaluation of the biological response of propofol in zebrafish (Danio rerio): Focusing on biochemical, transcriptional, and molecular level.

Propofol, one of the most widely used intravenous anesthetic in clinical practice, has been reported to impair cognitive and memory function. However, the toxicological effects of propofol on aquatic organisms are still poorly understood. This study explored the toxic effects of chronic propofol exposure (0.008, 0.04, and 0.2 mg L-1) on adult zebrafish from biochemical, transcriptional, and molecular level after 7, 14, 21 and 28 days of exposure. Results indicated that the reactive oxygen species (ROS) levels were significantly upregulated during the 28 days exposure period, and excessive ROS caused lipid peroxidation, resulting in increased malondialdehyde (MDA) contents in the zebrafish brain. In order to relieve the oxidative damage induced by the excessive ROS, the activities of antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT)) were significantly activated, and detoxification enzyme (glutathione S-transferase, GST) activities showed an "activation-inhibition" trend. However, the antioxidant enzymes and detoxification enzyme system could not eliminate the excessive ROS in time and thus caused DNA damage in zebrafish brain. The olive tail moment (OTM) values displayed a "dose-response" relationship with propofol concentrations. Meanwhile, the transcription of related genes of Nrf2-Keap1 pathway was activated. Further molecular simulation experiments suggested that propofol could directly combine with SOD/CAT to change the activity of its biological enzyme. These findings indicated that zebrafish could regulate antioxidant capacity to combat oxidative stress at the early exposure stage, but the activity of antioxidant enzymes were significantly inhibited with the increase of propofol exposure time. Our results are of great importance for understanding toxicological effects of propofol on aquatic organisms.

Propofol protects rats against intra-cerebroventricular streptozotocin-induced cognitive dysfunction and neuronal damage.

BACKGROUND: Cognitive dysfunction is a severe issue of Alzheimer's disease. Thus, the present study was conducted to enumerate the protective effect of propofol (PPL) in rats against intra-cerebroventricular streptozotocin (STZ)-induced cognitive dysfunction and neuronal damage. MATERIALS AND METHODS: The effect of PPL was investigated to evaluate behavioural changes in STZ-induced cognitive dysfunction in Wistar rats using Object Recognition Task (ORT) for nonspatial, Morris Water Maze (MWM) for spatial and locomotor activity. The effect of PPL was also investigated on acetylcholine (ACh) esterase (AChE) activity and oxidative stress markers, e.g., nitrite, malonaldehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH). The level of pro-inflammatory cytokines, e.g., tumour necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6, was also studied in the PPL-treated group. The effect of PPL on the level of neurotransmitters, e.g., dopamine (DA), serotonin (5-HT), and norepinephrine (NE) and their metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) levels were also estimated in frozen hippocampal tissues by high-performance liquid chromatography. Histopathology analysis of neurons in the hippocampus of rats was performed using haematoxylin and eosin (H&E) staining. RESULTS: Propofol showed significant improvement in the spatial and nonspatial memory deficit of rats in the MWM test and ORT in rats. It also causes improvement in locomotor activity of rats by preserving ACh via inhibition of AChE. It also potentiates the expression of DA, 5-HT, and NE with a simultaneous reduction in the level of metabolites (DOPAC, HVA, and 5-HIAA). PPL showed a reduction of oxidative stress in rats by restoring the level of nitrite, SOD, MDA, and GSH near to normal. In the PPL-treated group, the level of TNF-α, IL-1ß, and IL-6 was found reduced in a dose-dependent manner. In histopathology analysis of neurons in the hippocampus of the STZ rats, PPL causes dose-dependent reduction of pyknosis in the nucleus, which confirmed the protective effect of PPL. CONCLUSIONS: The present study demonstrated that PPL could significantly attenuate cognitive dysfunction and neuronal damage in STZ-induced rats.

Function of connexin 43 and RhoA/LIMK2/Cofilin signaling pathway in transient changes of contraction and dilation of human umbilical arterial smooth muscle cells.

BACKGROUND: Post-induction hypotension, a common complication after propofol-based induction regimen, is a life-threatening challenge for anesthesiologists especially when unexpected pre-induction hypertension characterized by angiotensin release and increased vascular tone was presented by the same patient. Gap junctions (GJs) composed of connexin 43 (Cx43) have been considered a key factor in regulating vascular contraction and dilation. We aimed to explore the role of Cx43-GJs during peri-induction blood pressure fluctuation and elucidate the underlying mechanisms. METHODS: Human umbilical arterial smooth muscle cells (HUASMCs) were pretreated by short-term Angiotensin Ⅱ (Ang Ⅱ) with or without subsequent propofol treatment to simulate transient contraction and dilation of vascular smooth muscle cells during anesthesia induction. F-actin polymerization, a classic indicator of HUASMCs constriction, was determined by F-actin staining assay. Both the function and expression of Cx43-GJs during transient contraction and dilation of HUASMCs, and their potential regulation of downstream Ca2+/RhoA/LIMK2/Cofilin signaling pathway were explored via different targeting inhibitors and siRNAs. RESULTS: Ang Ⅱ pretreatment significantly induced F-actin polymerization that indicate cell contraction, accompanied by enhanced GJs function on HUASMCs. With the inhibition of Cx43 GJs by the specific inhibitor, Gap26, and Cx43-siRNA, Ang Ⅱ-induced F-actin polymerization was reversed accompanied with the decrease of intracellular Ca2+ mobility and the RhoA/LIMK2/Cofilin signaling pathway activity. We also noticed that propofol application could inhibit GJs function, the same as Gap26. Simultaneously, intracellular Ca2+ mobility and RhoA/LIMK2/Cofilin signaling pathway activity on HUASMCs were both downregulated, finally resulting in downstream reduction of F-actin polymerization. CONCLUSION: The function of Cx43-GJs lies in the center of Ang Ⅱ-induced contraction of HUASMCs, which potentially regulates intracellular Ca2+ mobility as well as RhoA/LIMK2/Cofilin signaling pathway activity. Propofol can reverse this effect induced by Ang Ⅱ through suppressing the function of Cx43-GJs.

Propofol attenuates kinesin-mediated axonal vesicle transport and fusion.

Propofol is a widely used general anesthetic, yet the understanding of its cellular effects is fragmentary. General anesthetics are not as innocuous as once believed and have a wide range of molecular targets that include kinesin motors. Propofol, ketamine, and etomidate reduce the distances that Kinesin-1 KIF5 and Kinesin-2 KIF3 travel along microtubules in vitro. These transport kinesins are highly expressed in the CNS, and their dysfunction leads to a range of human pathologies including neurodevelopmental and neurodegenerative diseases. While in vitro data suggest that general anesthetics may disrupt kinesin transport in neurons, this hypothesis remains untested. Here we find that propofol treatment of hippocampal neurons decreased vesicle transport mediated by Kinesin-1 KIF5 and Kinesin-3 KIF1A ∼25-60%. Propofol treatment delayed delivery of the KIF5 cargo NgCAM to the distal axon. Because KIF1A participates in axonal transport of presynaptic vesicles, we tested whether prolonged propofol treatment affects synaptic vesicle fusion mediated by VAMP2. The data show that propofol-induced transport delay causes a significant decrease in vesicle fusion in distal axons. These results are the first to link a propofol-induced delay in neuronal trafficking to a decrease in axonal vesicle fusion, which may alter physiological function during and after anesthesia.

Integrated Excitatory/Inhibitory Imbalance and Transcriptomic Analysis Reveals the Association between Dysregulated Synaptic Genes and Anesthetic-Induced Cognitive Dysfunction.

Emerging evidence from human epidemiologic and animal studies has demonstrated that developmental anesthesia neurotoxicity could cause long-term cognitive deficits and behavioral problems. However, the underlying mechanisms remain largely unknown. We conducted an electrophysiological analysis of synapse activity and a transcriptomic assay of 24,881 mRNA expression on hippocampal tissues from postnatal day 60 (P60) mice receiving propofol exposure at postnatal day 7 (P7). We found that developmentally propofol-exposed P60 mouse hippocampal neurons displayed an E/I imbalance, compared with control mice as evidenced by the decreased excitation and increased inhibition. We found that propofol exposure at P7 led to the abnormal expression of 317 mRNAs in the hippocampus of P60 mice, including 23 synapse-related genes. Various bioinformatic analyses revealed that these abnormally expressed synaptic genes were associated with the function and development of synapse activity and plasticity, E/I balance, behavior, and cognitive impairment. Our findings suggest that the altered E/I balance may constitute a mechanism for propofol-induced long-term impaired learning and memory in mice. The transcriptomic and bioinformatic analysis of these dysregulated genes related to synaptic function paves the way for development of therapeutic strategies against anesthetic neurodegeneration through the restoration of E/I balance and the modification of synaptic gene expression.

Protection of propofol on liver ischemia reperfusion injury by regulating Cyp2b10/ Cyp3a25 pathway.

To verify whether propofol alleviates liver ischemia-reperfusion injury (IRI) in mice by regulating Cyp2b10/ Cyp3a25 pathway. The liver I/R injury in vivo and in vitro model was constructed. The serum level of AST, ALT, ALP and ALB was detected using ELISA. The mRNA and protein expression of Cyp2b10 and Cyp3a25 were determined by qRT-PCR and western blot, respectively. The liver cell activity was assessed by MTT assay. The binding between Cyp2b10 and Cyp3a25 was evaluated by online website prediction, CoIP, and cell transfection with Cyp2b10 siRNA and pcDNA3.1-Cyp3a25. The hepatocyte apoptosis was examined using flow cytometry assay. The serum level of AST, ALT, ALP was increased and that of ALB was decreased in liver I/R injury in vivo model. Also, the mRNA and protein expression of Cyp2b10 and Cyp3a25 were enhanced and reduced in liver I/R injury in vivo and vitro model respectively. The liver cell activity was markedly reduced in H/R cell model. However, these changes were all reversed with propofol treatment. Furthermore, Cyp2b10 could directly bind to Cyp3a25 to regulate the H/R-induced hepatocyte apoptosis. Propofol plays an effect of on liver I/R injury by regulating Cyp2b10/ Cyp3a25 pathway.

Involvement of the ERK signaling pathways in the NAc in propofol-seeking behavior induced by cues in rats.

Propofol, an intravenous short-acting anesthetic, has the potential to induce craving and relapse. Accumulated evidence demonstrates that extracellular signal-regulated kinase (ERK) plays an essential role in drug reward and relapse. In the previous study, we demonstrated that the ERK signaling pathways in the Nucleus accumbens (NAc) were involved in propofol reward. However, the role of the ERK signaling pathways in propofol relapse is still unknown. We first trained rats to self-administer propofol for 14 days, then evaluated propofol-seeking behavior of relapse induced by a contextual cues and conditioned cues after 14-day withdrawal. Meanwhile, MEK inhibitor U0126 was used to investigate the role of the ERK signal pathways in propofol-seeking behavior induced by contextual cues and conditioned cues. Results showed that the number of active nose-poke responses in propofol-seeking behavior induced by conditioned cues was much higher compared to contextual cues. U0126 (5.0 µg/side, Lateral Ventricle (LV)) pretreatment significantly decreased the active responses induced by conditioned cues, which was associated with a large decline in the expression of p-ERK in the NAc. Moreover, microinjectionofU0126 (2.0 µg/side) in the NAc also attenuated the active responses of propofol-seeking behavior. Additionally, microinjections with U0126 in the LV (5.0 µg/side) or NAc (2.0 µg/side) both failed to alter sucrose self-administration or locomotor activity of rats. Therefore, we conclude that ERK phosphorylation in the NAc maybe involved in propofol relapse.

Propofol enhances stem-like properties of glioma via GABAAR-dependent Src modulation of ZDHHC5-EZH2 palmitoylation mechanism.

BACKGROUND: Propofol is a commonly used anesthetic. However, its effects on glioma growth and recurrence remain largely unknown. METHODS: The effect of propofol on glioma growth was demonstrated by a series of in vitro and in vivo experiments (spheroidal formation assay, western blotting, and xenograft model). The acyl-biotin exchange method and liquid chromatography-mass spectrometry assays identified palmitoylation proteins mediated by the domain containing the Asp-His-His-Cys family. Western blotting, co-immunoprecipitation, quantitative real-time polymerase chain reaction, co-immunoprecipitation, chromatin immunoprecipitation, and luciferase reporter assays were used to explore the mechanisms of the γ-aminobutyric acid receptor (GABAAR)/Src/ZDHHC5/EZH2 signaling axis in the effects of propofol on glioma stem cells (GSCs). RESULTS: We found that treatment with a standard dose of propofol promoted glioma growth in nude mice compared with control or low-dose propofol. Propofol-treated GSCs also led to larger tumor growth in nude mice than did vector-treated tumors. Mechanistically, propofol enhances the stem-like properties of gliomas through GABAAR to increase Src expression, thereby enhancing the palmitoylation of ZDHHC5-mediated EZH2 and Oct4 expression. CONCLUSION: These results demonstrate that propofol may promote glioma growth through the GABAAR-Src-ZDHHC5-EZH2 mechanism and are helpful in guiding the clinical use of propofol to obtain a better patient prognosis after the surgical resection of tumors.

Effects of Minocycline on Cognitive Impairment, Hippocampal Inflammatory Response, and Hippocampal Alzheimer's Related Proteins in Aged Rats after Propofol Anesthesia.

The aim of this study was to evaluate the effect of minocycline preadministration on cognitive dysfunction, hippocampal inflammatory response, and hippocampal senile dementia-related proteins induced by propofol anesthesia in aged rats. Sixty male SD rats, aged 20 months and weighing 340-410 g, were randomly divided into three groups: normal saline (NC) group, propofol group (prop), and minocycline (M) group. Prop group rats were injected intraperitoneally with 100 mg/kg propofol. The rats in group M were injected intraperitoneally with 50 mg/kg minocycline 30 minutes before injection of 100 mg/kg propofol, and the rest were the same as prop group. The rats in NC group were received intraperitoneal injection of the same amount of normal saline. The results indicated that compared with group C, the expressions of GSK-3ß, acetyl-NF-κB (Lys310), Tau, and Amlyoid-beta were upregulated, the levels of TNF-α, IL-1ß, and IL-6 were increased, the escape incubation period was prolonged, and the exploration time was shortened in prop group, while the expression of GSK-3ß, acetyl-NF-κB (Lys310), Tau, and Amlyoid-beta in minocycline group was downregulated, the levels of TNF-α, IL-1ß, and IL-6 were decreased, the escape incubation period was shortened, and the exploration time was shortened. In conclusion, preadministration of minocycline can improve cognitive impairment induced by propofol anesthesia in aged rats, and its mechanism of action may be related to minocycline inhibiting hippocampal inflammatory reaction and downregulating the expression of GSK-3ß, acetyl-NF-κB (Lys310), Tau, and Amlyoid-beta proteins in hippocampus.

Neonatal Exposure to Propofol Interferes with the Proliferation and Differentiation of Hippocampal Neural Stem Cells and the Neurocognitive Function of Rats in Adulthood via the Akt/p27 Signaling Pathway.

Objective: Neonatal exposure to propofol has been reported to cause neurotoxicity and neurocognitive decline in adulthood; however, the underlying mechanism has not been established. Methods: SD rats were exposed to propofol on postnatal day 7 (PND-7). Double-immunofluorescence staining was used to assess neurogenesis in the hippocampal dentate gyrus (DG). The expression of p-Akt and p27 were measured by western blotting. The Morris water maze, novel object recognition test, and object location test were used to evaluate neurocognitive function 2-month-old rats. Results: Phosphorylation of Akt was inhibited, while p27 expression was enhanced after neonatal exposure to propofol. Propofol also inhibited proliferation of neural stem cells (NSCs) and decreased differentiation to neurons and astroglia. Moreover, the neurocognitive function in 2-month-old rats was weakened. Of significance, intra-hippocampal injection of the Akt activator, SC79, attenuated the inhibition of p-AKT and increase of p27 expression. SC79 also rescued the propofol-induced inhibition of NSC proliferation and differentiation. The propofol-induced neurocognition deficit was also partially reversed by SC79. Conclusion: Taken together, these results suggest that neurogenesis is hindered by neonatal propofol exposure. Specifically, neonatal propofol exposure was shown to suppress the proliferation and differentiation of NSCs by inhibiting Akt/p27 signaling pathway.

The effects of thiamine pyrophosphate on propofol-induced oxidative liver injury and effect on dysfunction.

Propofol may cause an increase in reactive oxygen species in the body. In this study, we tested the effect of antioxidant thiamine pyrophosphate (TPP) on propofol-induced liver damage. The eighteen rats were split into three groups: HG, healthy; PP, propofol-treated (50 mg/kg) and PT, treated with propofol (50 mg/kg) and TPP (25 mg/kg). Total glutathione (tGSH), total oxidant (TOS), and total antioxidant (TAS) levels were tested together with aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and malondialdehyde (MDA). Histopathological examination of the tissues was performed. We have found that levels of MDA, TOS, ALT, AST, and LDH were all higher in PP group than in HG and PT groups (p < 0.05). In PP group, the TAS and tGSH levels were statistically substantially lower. The PT for oxidants levels showed a statistically significant reduction. In PT group, the levels of antioxidants were found to be considerably higher. The epitheliums, glands, and vascular structures of the PTs were histologically close to normal. By boosting antioxidants, TPP may help to reduce propofolinduced liver damage.