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1.
Life Sci ; 244: 117280, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31926239

RESUMO

AIMS: Recently, chemoresistance has been recognized as an obstacle in the treatment of gastric cancer (GC). The aim of this study was to investigate the biological functions and underlying mechanisms of propofol in GC chemoresistance. MAIN METHODS: CCK-8 assay, flow cytometry and immunofluorescent staining were performed to assess the IC50 concentration, cell apoptosis and autophagy activity of cisplatin in both GC chemosensitive cells (SGC7901) and chemoresistant cells (SGC7901/CDDP). The expression pattern of MALAT1 in GC cells was detected by qRT-PCR. The shRNAs and overexpressing plasmids were employed for the loss or gain-of-function. Dual-luciferase reporter assay was subjected to verify the binding relationship between MALAT1 and miR-30e. Besides, ATG5 mRNA and protein levels were determined using qRT-PCR and western blot analysis. Furthermore, GC xenograft mice model was established to validate the in vitro findings. KEY FINDINGS: Chemoresistant GC cells presented higher IC50 of cisplatin, increased autophagy activity and stronger expression of MALAT1. The application of propofol promoted cell apoptosis and reduced the activity of autophagy through downregulating MALAT1. Silencing of MALAT1 inhibited chemo-induced autophagy, whereas MALAT1 overexpression promoted autophagy in GC cells. Mechanistic researches demonstrated that MALAT1 could bind with miR-30e to regulate ATG5 expression, thus causing the suppression of autophagy. In vivo GC xenograft model treated with both propofol and cisplatin also showed significantly decreased tumor size and weight, which was enhanced by knockdown of MALAT1. SIGNIFICANCE: Altogether, our study revealed a novel mechanism of propofol of lncRNA MALAT1/miR-30e/ATG5 mediated autophagy-related chemoresistance in GC, casting new lights on the understanding of propofol.


Assuntos
MicroRNAs/genética , Propofol/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/genética , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , China , Cisplatino/metabolismo , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , Propofol/farmacologia , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Toxicol Lett ; 322: 98-103, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31954869

RESUMO

Patients intoxicated with organophosphorous compounds may need general anaesthesia to enable mechanical ventilation or for control of epileptiform seizures. It is well known that cholinergic overstimulation attenuates the efficacy of general anaesthetics to reduce spontaneous network activity in the cortex. However, it is not clear how propofol, the most frequently used intravenous anaesthetic today, is affected. Here, we investigated the effects of cholinergic overstimulation induced by soman and acetylcholine on the ability of propofol to depress spontaneous action potential activity in organotypic cortical slices measured by extracellular voltage recordings. Cholinergic overstimulation by co-application of soman and acetylcholine (10 µM each) did not reduce the relative inhibition of propofol (1.0 µM; mean normalized action potential firing rate 0.49 ± 0.06 of control condition, p < 0.001, Wilcoxon signed rank test) but clearly reduced its efficacy. Co-application of atropine (10 nM) did not improve the efficacy. Propofol preserved its relative inhibitory potential but did not produce a degree of neuronal depression which can be expected to assure hypnosis in humans. Since a combination with atropine did not improve its efficacy, an increase in dosage will probably be necessary when propofol is used in victims suffering from organophosphorous intoxication.


Assuntos
Acetilcolina/toxicidade , Potenciais de Ação/efeitos dos fármacos , Anestésicos Intravenosos/farmacologia , Rede Nervosa/efeitos dos fármacos , Propofol/farmacologia , Soman/toxicidade , Acetilcolina/administração & dosagem , Anestesia Geral , Anestésicos Intravenosos/administração & dosagem , Animais , Camundongos Endogâmicos C57BL , Neocórtex/efeitos dos fármacos , Neocórtex/fisiologia , Rede Nervosa/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Técnicas de Cultura de Órgãos , Intoxicação por Organofosfatos , Propofol/administração & dosagem , Soman/administração & dosagem
3.
Life Sci ; 241: 117143, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31811855

RESUMO

AIM: To investigate the effect of propofol on the migration and invasion of oral squamous cell carcinoma (OSCC) cells and explore the underlying mechanism. MAIN METHODS: Cal-27 and SCC-25 cells treated with or without propofol, then the cells metastasis were determined. The levels of SNAI1 mRNA and protein were detected by real-time PCR and western blot. Cell migration ability was evaluated by wound healing assay, and the invasion of cells was measured using transwell assay. KEY FINDINGS: Propofol treatment significantly promoted cell migration and invasion of OSCC. Further mechanistic studies of the stimulating effects of propofol on OSCC cell metastasis revealed that propofol treatment dose-dependently upregulated the expression of SNAI1, a member of the Snail superfamily of zinc-finger transcription factors. Additionally, the inhibition of endogenous SNAI1 expression reversed the effect of propofol on cell migration and invasion in Cal-27 and SCC-25 cells. SIGNIFICANCE: Our results demonstrate that propofol at clinically relevant concentrations facilitates cell migration and invasion through up-regulation of SNAI1 in OSCC cells, and suggest propofol may not be suitable for anesthesia management in OSCC patients.


Assuntos
Carcinoma de Células Escamosas/patologia , Movimento Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Neoplasias Bucais/patologia , Propofol/farmacologia , Fatores de Transcrição da Família Snail/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Invasividade Neoplásica , Fatores de Transcrição da Família Snail/genética , Células Tumorais Cultivadas
4.
DNA Cell Biol ; 39(2): 197-209, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31880481

RESUMO

Propofol is a widely used intravenous agent for the induction and maintenance of anesthesia. An increasing number of studies have shown that propofol modulates autophagy, which is an evolutionarily conserved catabolic process that maintains cellular homeostasis by degrading long-lived proteins and damaged cellular proteins or organelles. Extensive studies have been performed to better understand the regulation of autophagy by propofol, the majority of which have demonstrated that the effects of propofol on autophagy are beneficial to organs and tissues. In this review, we retrospectively analyzed studies to assess the effects of propofol on autophagy in different diseases and evaluated the underlying mechanisms.


Assuntos
Autofagia/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Propofol/farmacologia , Animais , Autofagia/fisiologia , Sistema Nervoso Central/lesões , Humanos , Estudos Retrospectivos , Transdução de Sinais/efeitos dos fármacos
5.
Medicine (Baltimore) ; 98(47): e18088, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31764844

RESUMO

The objective of this study is to compare the effects of paravertebral nerve block-propofol intravenous general anesthesia (PPA) and sevoflurane inhalation general anesthesia (SGA) on the expression of serum vascular endothelial growth factor (VEGF) and transforming growth factor beta (TGF-ß) in patients undergoing radical resection of lung cancer.Patients undergoing radical resection of lung cancer were divided into PPA group and SGA group. In PPA group, thoracic paraspinal nerve block was performed with 0.5% ropivacaine (2 mg/kg) before general anesthesia. Anesthesia was maintained with 2.5-3.5 µg/mL TCI of propofol. In SGA group, anesthesia was maintained with 1.0-1.5 MAC sevoflurane. The dosage of opioids during and 24 h after operation, the pain score at 2, 8, 24, 48, and 72 h after operation, and the concentrations of serum VEGF and TGF-ß before and 24 h after operation were observed in the two groups.The intraoperative dosage of remifentanil in PPA group was significantly less than that in SGA group (P < 0.05). The dosage of sufentanil in SGA group was significantly less than that in SGA group at 24 h after operation (P < 0.05). The VAS score at 2, 8, and 24 h after operation was significantly lower than that in SGA group (P < 0.05). The serum VEGF and TGF-ß concentration in PPA group was significantly lower than that in SGA group (P < 0.05).Thoracic paravertebral nerve block-propofol intravenous general anesthesia can reduce the dosage of opioids, improve the effect of postoperative analgesia, and reduce the serum concentration of tumor angiogenesis-related factors in patients undergoing radical resection of lung cancer.


Assuntos
Anestesia Geral/métodos , Anestésicos Inalatórios/administração & dosagem , Anestésicos Intravenosos/administração & dosagem , Neoplasias Pulmonares/cirurgia , Pneumonectomia , Propofol/administração & dosagem , Sevoflurano/administração & dosagem , Sevoflurano/farmacologia , Fator de Crescimento Transformador beta/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Anestesia por Inalação , Anestesia Intravenosa , Anestésicos Inalatórios/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculos Paraespinais/inervação , Pneumonectomia/métodos , Propofol/farmacologia , Estudos Prospectivos , Tórax
6.
Yonsei Med J ; 60(12): 1195-1202, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31769251

RESUMO

PURPOSE: The aim of this study was to investigate whether propofol could attenuate hypoxia/reoxygenation-induced apoptosis and autophagy in human renal proximal tubular cells (HK-2) by inhibiting JNK activation. MATERIALS AND METHODS: HK-2 cells were treated with or without propofol or JNK inhibitor SP600125 for 1 hour and then subjected to 15 hours of hypoxia and 2 hours of reoxygenation (H/R). Cell viability and LDH release were measured with commercial kits. Cell apoptosis was evaluated by flow cytometry. The expressions of p-JNK, cleaved-caspase-3, Bcl-2, and autophagy markers LC3 and p62 were measured by Western blot or immunofluorescence. RESULTS: HK-2 cells exposed to H/R insult showed higher cell injury (detected by increased LDH release and decreased cell viability), increased cell apoptosis index and expression of cleaved-caspase-3, a decrease in the expression of Bcl-2 accompanied by increased expression of p-JNK and LC3II, and a decrease in expression of p62. All of these alterations were attenuated by propofol treatment. Similar effects were provoked upon treatment with the JNK inhibitor SP600125. Moreover, the protective effects were more obvious with the combination of propofol and SP600125. CONCLUSION: These results suggest that propofol could attenuate hypoxia/reoxygenation induced apoptosis and autophagy in HK-2 cells, probably through inhibiting JNK activation.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Propofol/farmacologia , Antracenos/farmacologia , Western Blotting , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , L-Lactato Desidrogenase/metabolismo , Oxigênio
7.
Artif Cells Nanomed Biotechnol ; 47(1): 3985-3993, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31583913

RESUMO

Propofol, an intravenous anaesthetic agent, has been found to exhibit antitumour effects in various kinds of cancer cells. However, the potential roles and regulatory mechanisms of propofol in oral squamous cell carcinoma (OSCC) remain unknown. Herein, we found that propofol inhibits OSCC cell growth and promotes cell apoptosis in a dose- and time-dependent manner. Further mechanistic studies revealed that the long noncoding RNA GAS5 is induced by propofol in OSCC cells. Elevated GAS5 acts as a competing endogenous RNA for miR-1297 and attenuates its inhibitory effect on GSK3ß, leading to GSK3ß increase and Mcl1 decrease. Additionally, we found that FoxO1 binds to the promoter of GAS5, facilitating its transcription in response to propofol treatment. Thus, these results suggest that propofol exhibits antitumour effects in OSCC cells and that the FoxO1-GAS5-miR-1297-GSK3ß axis plays an important role in propofol-induced OSCC cell apoptosis.


Assuntos
Apoptose/genética , Carcinoma de Células Escamosas/patologia , Glicogênio Sintase Quinase 3 beta/metabolismo , MicroRNAs/genética , Neoplasias Bucais/patologia , Propofol/farmacologia , RNA Longo não Codificante/genética , Antineoplásicos/farmacologia , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Proteína Forkhead Box O1/metabolismo , Humanos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
8.
J Stroke Cerebrovasc Dis ; 28(12): 104375, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31590996

RESUMO

BACKGROUND: Our previous study showed that propofol, one of the widely used anesthetic agents, can attenuate subarachnoid hemorrhage (SAH)-induced early brain injury (EBI) via inhibiting inflammatory and oxidative reaction. However, it is perplexing whether propofol attenuates inflammatory and oxidative reaction through modulating PI3K/Akt pathway. The present study investigated whether PI3K/Akt pathway is involved in propofol's anti-inflammation, antioxidation, and neuroprotection against SAH-induced EBI. MATERIALS AND METHODS: Adult Sprague-Dawley rats underwent SAH and received treatment with propofol or vehicle after 2 and 12 hours of SAH. LY294002 was injected intracerebroventricularly to selectively inhibit PI3K/Akt signaling. Mortality, SAH grading, neurological scores, brain water content, evans blue extravasation, myeloperoxidase, malondialdehyde, superoxide dismutase, and glutathione peroxidase were measured 24 hours after SAH. Immunoreactivity of p-Akt, t-Akt, nuclear factor- kappa B (NF-κB) p65, nuclear factor erythroid-related factor 2 (Nrf2), NAD(P)H:quinone oxidoreductase (NQO1), and cyclooxygenase-2 (COX-2) in rat brain was determined by western blot. Tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in rat brain were examined by ELISA. RESULTS: Propofol significantly reduces neurological dysfunction, BBB permeability, brain edema, inflammation, and oxidative stress, all of which were reversed by LY294002. Propofol significantly upregulates the immunoreactivity of p-Akt, Nrf2, and NQO1, all of which were abolished by LY294002. Propofol significantly downregulates the overexpression of NF-κB p65, COX-2, TNF-α, and IL-1ß, all of which were inhibited by LY294002. CONCLUSION: These results suggest that propofol attenuates SAH-induced EBI by inhibiting inflammatory reaction and oxidative stress, which might be associated with the activation of PI3K/Akt signaling pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Edema Encefálico/prevenção & controle , Encéfalo/efeitos dos fármacos , Encefalite/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Propofol/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Hemorragia Subaracnóidea/tratamento farmacológico , Animais , Encéfalo/enzimologia , Encéfalo/patologia , Edema Encefálico/enzimologia , Edema Encefálico/patologia , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Encefalite/enzimologia , Encefalite/patologia , Interleucina-1beta/metabolismo , Masculino , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Ratos Sprague-Dawley , Transdução de Sinais , Hemorragia Subaracnóidea/enzimologia , Hemorragia Subaracnóidea/patologia , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
9.
Neurol Res ; 41(11): 1008-1014, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31573411

RESUMO

Objective: To investigate the effects of propofol used in early pregnancy on brain development and function of offspring, and further to explore the effects of docosahexaenoic acid (DHA) intervention. Methods: Forty pregnant rats were randomly divided into four groups: control group (C), propofol group (P), DHA intervention group (D), and propofol + DHA group (P + D). The DHA treatment was before propofol was administered. Morris water maze test was performed 30 days after delivery. The levels of amyloid beta (Aß), IL-1ß and reactive oxygen species (ROS) in hippocampus were detected by enzyme-linked immunosorbent assay (ELISA). The expression of brain-derived neurotrophic factor (BDNF) and tyrosine kinase-B (Trk-B), protein kinase B (Akt), p-Akt and cAMP response element-binding protein (CREB) in hippocampus were detected by western blot. Results: The learning and memory abilities of the rats in P group were reduced. The levels of Aß, IL-1ß and ROS were increased, while the levels of BDNF, Trk-B and CREB, and p-Akt/Akt ratio were reduced. In addition, compared with P group, DHA in P + D group reversed or alleviated adverse changes caused by propofol. Conclusions: Application of general anesthesia with propofol during the early stage of pregnancy can negatively affect the brain development of the offspring to reduce the learning and memory ability, while DHA can reverse it.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Memória/efeitos dos fármacos , Propofol/farmacologia , Anestesia Geral/métodos , Animais , Animais Recém-Nascidos , Encéfalo/crescimento & desenvolvimento , Feminino , Hipocampo/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Gravidez , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
10.
Acta Biochim Biophys Sin (Shanghai) ; 51(11): 1114-1122, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31650167

RESUMO

Propofol is one of the most commonly used intravenous anesthetics and plays an important role in tumor suppression. In the present study, we aimed to investigate the mechanism by which propofol attenuates tumor endothelial cells (TECs) and tumor cell adhesion to inhibit tumor metastasis in vitro. Human umbilical vein endothelial cells (HUVECs) cultured in Dulbecco's modified Eagle's medium were treated with tumor conditioned medium for 24 h, followed by 4 h of treatment with or without 25 µM of propofol, 10 µM of KN93, 500 µM of MK801, or 20 µM of rapastinel. It was found that propofol inhibited TEC adhesion and the glycolysis level of TECs. Consistently, propofol inhibited the expressions of adhesion molecules (E-selectin, ICAM-1, and VCAM-1) and glycolysis proteins (GLUT1, HK2, and LDHA) in TECs. Moreover, propofol attenuated the expression of HIF-1α, the phosphorylation of AKT and Ca2+/calmodulin-dependent protein kinase II (CaMKII), and the Ca2+ concentration in TECs. MK801, an inhibitor of NMDA receptor, and KN93, an inhibitor of CaMKII, both inhibited the expressions of adhesion molecules and glycolysis proteins, in a manner similar to propofol. Additionally, rapastine, an activator of NMDA receptor, could counteract the effects of propofol. Our results indicated that propofol attenuates intracellular Ca2+ concentration, CaMKII and AKT phosphorylation, and HIF-1α expression, probably via inhibiting the NMDA receptor, thus inhibiting glycolysis and adhesion of tumor and endothelial cells.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Adesão Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Propofol/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Glicólise/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
11.
Nat Commun ; 10(1): 4616, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601811

RESUMO

Prominent theories of consciousness emphasise different aspects of neurobiology, such as the integration and diversity of information processing within the brain. Here, we combine graph theory and dynamic functional connectivity to compare resting-state functional MRI data from awake volunteers, propofol-anaesthetised volunteers, and patients with disorders of consciousness, in order to identify consciousness-specific patterns of brain function. We demonstrate that cortical networks are especially affected by loss of consciousness during temporal states of high integration, exhibiting reduced functional diversity and compromised informational capacity, whereas thalamo-cortical functional disconnections emerge during states of higher segregation. Spatially, posterior regions of the brain's default mode network exhibit reductions in both functional diversity and integration with the rest of the brain during unconsciousness. These results show that human consciousness relies on spatio-temporal interactions between brain integration and functional diversity, whose breakdown may represent a generalisable biomarker of loss of consciousness, with potential relevance for clinical practice.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Transtornos da Consciência/diagnóstico por imagem , Estado de Consciência , Adolescente , Adulto , Idoso , Anestésicos Intravenosos/farmacologia , Encéfalo/efeitos dos fármacos , Transtornos da Consciência/fisiopatologia , Entropia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Propofol/farmacologia , Inconsciência/diagnóstico por imagem , Inconsciência/fisiopatologia , Vigília , Adulto Jovem
12.
J Biomed Sci ; 26(1): 74, 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31627754

RESUMO

BACKGROUND: Complex regional pain syndrome (CRPS) is related to microcirculation impairment caused by tissue hypoxia and peripheral cytokine overproduction in the affected human limb and chronic post-ischemic pain (CPIP) is considered as an animal model for this intractable disease. Previous studies suggest that the pathogenesis of CPIP involves the hypoxia inducible factor-1α (HIF-1α) and an exaggerated regional inflammatory and free radical response. The inhibition of HIF-1α is known to relieve CPIP. So, propofol, as a free radical scavenger, is very likely to be beneficial in terms of relieving CPIP. METHODS: We set up a CPIP model using the hindpaw of mice. We administered propofol (10 mg/kg) just after the reperfusion period (early stage) and also on the second day (late stage), as treatment. The analysis evaluated the expression of HIF-1α, free radicals, and inflammasome. RESULTS: Propofol administration produced obvious analgesia in both mechanical and thermal evaluation in the early stage of CPIP (2 h after reperfusion). Only a mild analgesic effect was found in the late stage (48 h later after reperfusion). In the early stage, the expression of HIF-1α and the inflammasome marker (NALP1) along with caspase-1 were suppressed by propofol. The free radical level also decreased in the propofol group. But those molecular changes were not founded in the late stage of CPIP. CONCLUSION: Our data demonstrated that propofol produces mice analgesia in the early stage of CPIP and this effect is associated with inhibition of free radical, hypoxia inducible factor and inflammasome.


Assuntos
Analgesia , Síndromes da Dor Regional Complexa/tratamento farmacológico , Hipnóticos e Sedativos/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Inflamassomos/genética , Propofol/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Administração Intravenosa , Anestésicos Intravenosos/farmacologia , Animais , Depuradores de Radicais Livres/farmacologia , Regulação da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamassomos/metabolismo , Masculino , Camundongos
13.
Artigo em Inglês | MEDLINE | ID: mdl-31540542

RESUMO

Abstract: Recent evidences suggest that non-arousal mechanisms can restore and stabilize breathing in sleeping patients with obstructive sleep apnea. This possibility can be examined under deep sedation which increases the cortical arousal threshold. We examined incidences of cortical arousal at termination of apneas and hypopneas in elderly patients receiving propofol sedation which increases the cortical arousal threshold. Ten elderly patients undergoing advanced endoscopic procedures under propofol-sedation were recruited. Standard polysomnographic measurements were performed to assess nature of breathing, consciousness, and occurrence of arousal at recovery from apneas and hypopneas. A total of 245 periodic apneas and hypopneas were identified during propofol-induced sleep state. Cortical arousal only occurred in 55 apneas and hypopneas (22.5%), and apneas and hypopneas without arousal and desaturation were most commonly observed (65.7%) regardless of the types of disordered breathing. Chi-square test indicated that incidence of no cortical arousal was significantly associated with occurrence of no desaturation. Higher dose of propofol was associated with a higher apnea hypopnea index (r = 0.673, p = 0.033). In conclusion, even under deep propofol sedation, apneas and hypopneas can be terminated without cortical arousal. However, extensive suppression of the arousal threshold can lead to critical hypoxemia suggesting careful respiratory monitoring.


Assuntos
Nível de Alerta/fisiologia , Hidrocortisona/biossíntese , Propofol/farmacologia , Síndromes da Apneia do Sono/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polissonografia , Propofol/administração & dosagem , Estudos Prospectivos , Respiração
14.
Biomed Res Int ; 2019: 7587451, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31380437

RESUMO

Nowadays, the prevention of severe myocardium injury resulting from myocardial ischemia/reperfusion injury (I/R) has been recognized as an important subject in the field of ischemic heart disease. In this study, H9c2 cardiomyocytes were exposed to cycles of hypoxia/reoxygenation (H/R) to mimic myocardial I/R injury. Western blot analysis and qRT-PCR were performed to detect the expression of Cox-2, Akt and p-Akt. Cell viability, LDH release and activity of Caspase-3 were assessed to determine the protective effect of propofol. The results proved that the protective effect of propofol for H/R challenged cardiomyocytes was associated with Akt phosphorylation. We also revealed that treatment of propofol suppressed the expression of Cox-2 in cardiomyocytes which was up-regulated after H/R treatment. Conversely, the over-expression of Cox-2 inhibited Akt phosphorylation while enhancing cardiomyocytes apoptosis. Interestingly, Akt activator exhibited similar protective effect with propofol and could diminish the influences brought by over-expression of Cox-2. Thus, it could be concluded that Cox-2 negatively affects the protective effect of propofol against hypoxia/reoxygenation induced cardiomyocyte apoptosis by suppressing Akt phosphorylation.


Assuntos
Ciclo-Oxigenase 2/genética , Proteína Oncogênica v-akt/genética , Propofol/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/genética , Isquemia Miocárdica/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Fosforilação , Ratos , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia , Transdução de Sinais/efeitos dos fármacos
15.
Neurochem Res ; 44(9): 2147-2155, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31385137

RESUMO

Inhibitors of acetylcholinesterase (AChE), which have an important role in the prevention of excessive AChE activity and ß-amyloid (Aß) formation are widely used in the symptomatic treatment of Alzheimer's disease (AD). The inhibitory effect of anesthetic agents on AChE was determined by several approaches, including binding mechanisms, molecular docking and kinetic analysis. Inhibitory effect of intravenous anesthetics on AChE as in vitro and in vivo have been discovered. The midazolam, propofol and thiopental have shown competitive inhibition type (midazolam > propofol > thiopental) and Ki values were found to be 3.96.0 ± 0.1, 5.75 ± 0.12 and 29.65 ± 2.04 µM, respectively. The thiopental and midazolam showed inhibition effect on AChE in vitro, whereas they showed activation effect in vivo when they are combined together. The order of binding of the drugs to the active site of the 4M0E receptor was found to be midazolam > propofol > thiopental. This study on anesthetic agents that are now widely used in surgical applications, have provided a molecular basis for investigating the drug-enzyme interactions mechanism. In addition, the study is important in understanding the molecular mechanism of inhibitors that are effective in the treatment of AD.


Assuntos
Acetilcolinesterase/metabolismo , Anestésicos Intravenosos/farmacologia , Inibidores da Colinesterase/farmacologia , Midazolam/farmacologia , Propofol/farmacologia , Tiopental/farmacologia , Acetilcolinesterase/química , Adulto , Anestésicos Intravenosos/metabolismo , Domínio Catalítico , Inibidores da Colinesterase/metabolismo , Humanos , Cinética , Masculino , Midazolam/metabolismo , Simulação de Acoplamento Molecular , Propofol/metabolismo , Ligação Proteica , Tiopental/metabolismo , Adulto Jovem
16.
Biomed Pharmacother ; 118: 109308, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31401396

RESUMO

Remote preconditioning of trauma (RPCT) by surgical incision is an effective cardioprotective strategy via the transient receptor potential vanilloid 1 (TRPV1) channel as a form of remote ischemic preconditioning (RIPC). However, cardioprotection by RIPC has been shown to be completely blocked by propofol. We thus hypothesized that propofol may interfere with RPCT induced cardioprotection, and that RPCT induces cardioprotection via the cardiac TRPV1 channel. Male Sprague-Dawley rats were subjected to 30 min of myocardial ischemia followed by 2 h of reperfusion. RPCT was achieved by a transverse abdominal incision. Additionally, propofol or the TRPV1 receptor inhibitor capsazepine (CPZ) was given before RPCT. Infarct size was assessed by triphenyltetrazolium staining. Heart TRPV1 expression was detected by Western blot and immunofluorescence. RPCT significantly reduced infarct size compared to control treatment (45.6 ±â€¯4% versus 65.4 ±â€¯2%, P < 0.01). This protective effect of RPCT was completely abolished by propofol and CPZ. TRPV1 channels are present in the heart. Therefore, cardioprotection by RPCT is also abolished by propofol, and cardiac TRPV1 mediates this cardioprotection.


Assuntos
Cardiotônicos/farmacologia , Precondicionamento Isquêmico , Propofol/farmacologia , Canais de Cátion TRPV/metabolismo , Ferimentos e Lesões/patologia , Anestésicos/farmacologia , Animais , Hemodinâmica/efeitos dos fármacos , Masculino , Ratos Sprague-Dawley
17.
Mol Cell Biochem ; 462(1-2): 85-96, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31446614

RESUMO

Heat shock proteins (HSPs) may be induced by hypoxia and alleviate blood-brain barrier (BBB) damage. The neuroprotective effect of propofol has been reported. We aimed to identify whether propofol induced HSPs expression and protected BBB integrity. Mouse astrocytes and microglia cells were cultured and exposed to hypoxia and propofol. The expression of HSP27, HSP32, HSP70, and HSP90, and the translocation of heat shock factor 1 (HSF1) and Nuclear factor-E2-related factor 2 (Nrf2) were investigated. Mouse brain microvascular endothelial cells, astrocytes, and microglial cells were co-cultured to establish in vitro BBB model, and the effects of hypoxia and propofol as well as HSPs knockdown/overexpression on BBB integrity were measured. Hypoxia (5% O2, 5% CO2, 90% humidity) treatment for 6 h and 12 h induced HSP27, HSP32, and HSP70 expression. Propofol (25 µΜ) increased HSP27 and HSP32 expression, starting with exposure to hypoxia for 3 h. Propofol induced HSF1 translocation from cytoplasmic to nuclear compartment, and blockade of HSF1 inhibited HSP27 expression in mouse astrocytes when they were exposed to hypoxia for 3 h. Propofol induced Nrf2 translocation, and blockade of Nrf2 inhibited HSP32 expression in mouse microglial cells when they were exposed to hypoxia for 3 h. Propofol protected hypoxia-impaired BBB integrity, and the effects were abolished by blockade of HSF1 and Nrf2. Overexpression of HSP27 and HSP32 alleviated hypoxia-impaired BBB integrity, and blockade of HSP27 and HSP32 expression ameliorated propofol-mediated protection against BBB impairment. Propofol may protect hypoxia-mediated BBB impairment. The mechanisms may involve HSF1-mediated HSP27 expression and Nrf2-mediated HSP32 expression.


Assuntos
Barreira Hematoencefálica/metabolismo , Proteínas de Choque Térmico/metabolismo , Propofol/farmacologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Permeabilidade , Substâncias Protetoras/farmacologia
18.
Exp Mol Pathol ; 110: 104295, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31419406

RESUMO

BACKGROUND: We used a two-hit lung injury rat model that involves mechanical ventilation (MV) following lipopolysaccharide exposure to investigate the effects of propofol on the expression of GABAA receptors (GABAAR) and cytokine responses, and we then determined the specific effects of GABA on cytokine responses in vitro in alveolar epithelial cells (AECs). METHODS: Forty-eight adult male Wister rats were equally and randomly divided into the following 4 groups (n = 12) using a random number table: sham group, sham+propofol group, lipopolysaccharide (LPS) + VILI group, and LPS + VILI + propofol group. All animals were anesthetized, and the animals received a 3.75 mg/kg intratracheal instillation of endotoxins or phosphate-buffered saline (PBS) as the control, as described previously. After 30 min, rats were ventilated for 5 h in a volume-controlled ventilation mode. In the LPS + VILI group, animals were ventilated with a tidal volume (Vt) of 22 ml/kg and zero positive end-expiratory pressure (PEEP) at a respiratory rate of 16-18 breaths/min, whereas control (sham) rats were ventilated with a Vt of 6 ml/kg and PEEP of 5 cmH2O at a rate of 45-55 breaths/min. The FiO2 remained constant as 0.4, propofol was administered intravenously in the LPS + VILI + propofol and sham + propofol groups at a rate of 10 mg·kg-1·h-1 while normal saline at the same rate was intravenously administered in the LPS + VILI and sham groups during the entire mechanical ventilation period. Five hours after mechanical ventilation, the rats were killed. Survival rates, histopathology, concentrations of inflammatory mediators in bronchoalveolar lavage fluid (BALF), wet weight/dry weight (W/D) ratio of the lung, myeloperoxidase (MPO) activity in lung tissues, and expression of GAD and GABAAR by immunohistochemical detection and Western blotting were assessed. Then, human type II-like alveolar epithelial cells (A549 cells) were cultured to full confluence and incubated with GABA (100 nM) alone, picrotoxin alone, a GABAAR antagonist (PTX, 50 nM), or GABA + PTX for 10 min, followed by stimulation with LPS (control) at 100 ng/ml for 4 h. The concentrations of IL-1ß, IL-2, IL-8, and IL-10 were then measured. RESULTS: Administration of propofol in a two-hit lung injury rat model can increase survival rates and the expression of GAD and GABAAR (P < .05). The administration of propofol can attenuate the release of pro-inflammatory cytokines both in vivo and in vitro, and the administration of propofol can attenuate histopathological changes, the W/D ratio, and MPO activity (P < .05). CONCLUSIONS: In this study, we found that the administration of propofol improved lung function, alleviated lung injury, and up-regulated the GAD and GABAAR expressions in a two-hit model of acute lung injury (ALI) characterized by intratracheal instillation of an endotoxin and prolonged MV. Therefore, the protective effects of propofol may be associated with the up-regulation of GABAA receptors in AECs.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Propofol/farmacologia , Receptores de GABA-A/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Citocinas/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , Ratos , Ratos Wistar , Receptores de GABA-A/genética , Regulação para Cima
19.
J Biochem ; 166(5): 415-421, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31297532

RESUMO

Reducing oxidative stress is an effective method to prevent hepatic ischaemia/reperfusion injury (HIRI). This study focuses on the role of propofol on the oxidative stress of hepatic cells and the involved lncRNA-TUG1/Brahma-related gene 1 (Brg1) pathway in HIRI mice. The mouse HIRI model was established and was intraperitoneally injected with propofol postconditioning. Hepatic injury indexes were used to evaluate HIRI. The oxidative stress was indicated by increasing 8-isoprostane concentration. Mouse hepatic cell line AML12 was treated with hypoxia and subsequent reoxygenation (H/R). The targeted regulation of lncRNA-TUG1 on Brg1 was proved by RNA pull-down, RIP (RNA-binding protein immunoprecipitation) and the expression level of Brg1 responds to silencing or overexpression of lncRNA-TUG1. Propofol alleviates HIRI and induces the upregulation of lncRNA-TUG1 in the mouse HIRI model. Propofol increases cell viability and lncRNA-TUG1 expression level in H/R-treated hepatic cells. In H/R plus propofol-treated hepatic cells, lncRNA-TUG1 silencing reduces cell viability and increased oxidative stress. LncRNA-TUG1 interacts with Brg1 protein and keeps its level via inhibiting its degradation. Brg1 overexpression reverses lncRNA-TUG1 induced the reduction of cell viability and the increase in oxidative stress. LncRNA-TUG1 silencing abrogates the protective role of propofol against HIRI in the mouse HIRI model. LncRNA-TUG1 has a targeted regulation of Brg1, and thereby affects the oxidative stress induced by HIRI. This pathway mediates the protective effect of propofol against HIRI of hepatic cell.


Assuntos
DNA Helicases/metabolismo , Hepatócitos/efeitos dos fármacos , Hipóxia/tratamento farmacológico , Proteínas Nucleares/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxigênio/metabolismo , Propofol/farmacologia , RNA Longo não Codificante/metabolismo , Fatores de Transcrição/metabolismo , Animais , Hepatócitos/metabolismo , Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regulação para Cima/efeitos dos fármacos
20.
Life Sci ; 232: 116624, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276689

RESUMO

AIMS: Monocyte-endothelial adhesion is considered to be the primary initiator of inflammatory vascular diseases, such as atherosclerosis. Connexin 43 (Cx43) has been reported to play an important part in this process, however, the underlying mechanisms are not fully understood. Intravenous anesthetics, propofol is commonly used in the perioperative period and in the intensive care unit, and considered to have good anti-inflammatory and antioxidant effects. Thus, we speculate that propofol could influence monocyte-endothelial adhesion, and explore whether its possible mechanism is relative with Cx43 expression in U937 monocytes influencing cell adhesion of U937 monocytes to human umbilical vein endothelial cells (HUVEC). MAIN METHODS: Cx43-siRNAs or pc-DNA-Cx43 were used to alter Cx43 expression in U937 monocytes. Propofol was given as pretreatments to U937 monocytes. Then, cell adhesion, ZO-1, LFA-1, VLA-4, COX and MCP-1 were determined. PI3K/AKT/NF-κB signaling pathway was explored to clarify the possible mechanism. KEY FINDINGS: Alternation of Cx43 expression affects cell adhesion and adhesion molecules significantly, such as ZO-1, LFA-1, VLA-4, COX-2 and MCP-1, the mechanism of which is relative with Cx43 influencing the activation of PI3K/AKT/NF-κB signaling pathway. Preconditioning with propofol at its clinically relevant anesthesia concentration attenuates cell adhesion. Propofol not only decreases Cx43 expression in U937 monocytes, but also depresses the activation of PI3K/AKT/NF-κB signaling pathway. SIGNIFICANCE: Modulation Cx43 expression in U937 monocytes could affect cell adhesion via regulating the activation of PI3K/AKT/NF-κB signaling pathway. Propofol attenuates cell adhesion via inhibiting Cx43 and its downstream signaling pathway of PI3K/AKT/NF-κB.


Assuntos
Adesão Celular/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Propofol/farmacologia , Aterosclerose/metabolismo , Moléculas de Adesão Celular/metabolismo , Conexina 43/efeitos dos fármacos , Conexina 43/genética , Conexina 43/metabolismo , Endotélio Vascular/metabolismo , Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Monócitos/fisiologia , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Propofol/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células U937/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo
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