RESUMEN
A substantial proportion of diabetic patients suffer a debilitating and persistent pain state, known as peripheral painful neuropathy that necessitates improved therapy or antidote. Purpurin, a natural anthraquinone compound from Rubia tinctorum L., has been reported to possess antidepressant activity in preclinical studies. As antidepressants have been typically used as standard agents against persistent neuropathic pain, this study aimed to probe the effect of purpurin on neuropathic pain associated with streptozotocin-induced type 1 diabetes in male C57BL6J mice. The Hargreaves test and the von Frey test were used to assess the pain-like behaviors, shown as heat hyperalgesia and mechanical allodynia respectively. Chronic treatment of diabetic mice with purpurin not only ameliorated the established symptoms of heat hyperalgesia and mechanical allodynia, but also arrested the development of these pain states given preemptively at low doses. Although purpurin treatment hardly impacted on metabolic disturbance in diabetic mice, it ameliorated exacerbated oxidative stress in pain-associated tissues, improved mitochondrial bioenergetics in dorsal root ganglion neurons and restored nerve conduction velocity in sciatic nerves. Notably, the analgesic actions of purpurin were modified by pharmacologically manipulating redox status and mitochondrial bioenergetics. These findings unveil the analgesic activity of purpurin, an effect that is causally associated with its bioenergetics-enhancing and antioxidant effects, in mice with type 1 diabetes.
Asunto(s)
Antraquinonas , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Metabolismo Energético , Hiperalgesia , Ratones Endogámicos C57BL , Mitocondrias , Neuralgia , Neuronas , Oxidación-Reducción , Animales , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Metabolismo Energético/efectos de los fármacos , Oxidación-Reducción/efectos de los fármacos , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Antraquinonas/farmacología , Antraquinonas/uso terapéutico , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuropatías Diabéticas/tratamiento farmacológico , Neuropatías Diabéticas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Nervio Ciático/efectos de los fármacos , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Analgésicos/farmacología , Analgésicos/uso terapéuticoRESUMEN
BACKGROUND: Ventilator-induced lung injury (VILI) is caused by overdistension of the alveoli by the repetitive recruitment and derecruitment of alveolar units. This study aims to investigate the potential role and mechanism of fibroblast growth factor 21 (FGF21), a metabolic regulator secreted by the liver, in VILI development. METHODS: Serum FGF21 concentrations were determined in patients undergoing mechanical ventilation during general anesthesia and in a mouse VILI model. Lung injury was compared between FGF21-knockout (KO) mice and wild-type (WT) mice. Recombinant FGF21 was administrated in vivo and in vitro to determine its therapeutic effect. RESULTS: Serum FGF21 levels in patients and mice with VILI were significantly higher than in those without VILI. Additionally, the increment of serum FGF21 in anesthesia patients was positively correlated with the duration of ventilation. VILI was aggravated in FGF21-KO mice compared with WT mice. Conversely, the administration of FGF21 alleviated VILI in both mouse and cell models. FGF21 reduced Caspase-1 activity, suppressed the mRNA levels of Nlrp3, Asc, Il-1ß, Il-18, Hmgb1 and Nf-κb, and decreased the protein levels of NLRP3, ASC, IL-1ß, IL-18, HMGB1 and the cleaved form of GSDMD. CONCLUSIONS: Our findings reveal that endogenous FGF21 signaling is triggered in response to VILI, which protects against VILI by inhibiting the NLRP3/Caspase-1/GSDMD pyroptosis pathway. These results suggest that boosting endogenous FGF21 or the administration of recombinant FGF21 could be promising therapeutic strategies for the treatment of VILI during anesthesia or critical care.
Asunto(s)
Proteína HMGB1 , Lesión Pulmonar Inducida por Ventilación Mecánica , Animales , Ratones , Caspasa 1/metabolismo , Modelos Animales de Enfermedad , Inflamasomas , Interleucina-18 , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Lesión Pulmonar Inducida por Ventilación Mecánica/tratamiento farmacológico , Lesión Pulmonar Inducida por Ventilación Mecánica/prevención & control , HumanosRESUMEN
PURPOSE: Only few studies have analyzed the global distribution of anesthesia research. This study was designed to reveal the current global research status of anesthesiology. METHODS: Articles published between 1999 and 2018 in international journals in the field of anesthesiology were retrieved from the PubMed database. The top 20 ranked countries were identified. The gross domestic product (GDP) of each country was also retrieved to reveal the correlation between research outputs and the economy. The total outputs and outputs per 10 million inhabitants in each country were calculated and compared. To analyze the quality of publications among the top 10 ranked countries, the impact factor (IF), article influence score (AIS), and immediacy index (ImI) were calculated and analyzed. In addition, the keywords of publications were retrieved to conduct co-occurrence analysis in order to determine the research focus in anesthesiology. RESULTS: A total of 112,918 articles were published in 30 selected journals from 1999 to 2018. There was a positive correlation between research outputs and GDP of 10 countries (pâ¯< 0.001, râ¯= 0.825). The USA ranked 1st with 21,703 articles, followed by the UK (8393 articles) and Germany (6504 articles). Canada had the highest number of publications per 10 million inhabitants in 2018. The UK had the highest average IF (4.70), average AIS (1.16), and average ImI (1.64) among the 10 countries. The research highlights in the field of anesthesiology included "mechanism and management of pain", "cardiac anesthesia", "pediatric anesthesia and airway management", "analgesia" and "anesthetic agents". CONCLUSION: Regarding quantity trend, the output of global production in anesthesiology increased continuously as the number of articles from the high-output countries showed an increasing trend; however, there was still a gap between developing and developed countries in research quality. High-quality research should be encouraged in developing countries.
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Anestesia , Anestesiología , Bibliometría , Niño , Alemania , HumanosRESUMEN
Prostaglandin E receptor subtype 4 (EP4) is widely distributed in the heart, but its role in hepatic ischemia/reperfusion (I/R), particularly in mitochondrial permeability transition pore (MPTP) modulation, is yet to be elucidated. In the present study, an EP4 agonist (CAY10598) was used in a rat model to evaluate the effects of EP4 activation on liver I/R and the mechanisms underlying this. I/R insult upregulated hepatic EP4 expression during early reperfusion. In addition, subcutaneous CAY10598 injection prior to the onset of reperfusion significantly increased hepatocyte cAMP concentrations and decreased serum ALT and AST levels and necrotic and apoptotic cell percentages, after 6 h of reperfusion. Moreover, CAY10598 protected mitochondrial morphology, markedly inhibited mitochondrial permeability transition pore (MPTP) opening and decreased liver reactive oxygen species levels. This occurred via activation of the ERK1/2GSK3ß pathway rather than the janus kinase (JAK)2signal transducers and activators of transcription (STAT)3 pathway, and resulted in prevention of mitochondriaassociated cell injury. The MPTP opener carboxyatractyloside (CATR) and the ERK1/2 inhibitor PD98059 also partially reversed the protective effects of CAY10598 on the liver and mitochondria. The current findings indicate that EP4 activation induces ERK1/2GSK3ß signaling and subsequent MPTP inhibition to provide hepatoprotection, and these observations are informative for developing new molecular targets and preventative therapies for I/R in a clinical setting.
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Glucógeno Sintasa Quinasa 3 beta/metabolismo , Hígado/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial/metabolismo , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Daño por Reperfusión/metabolismo , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/fisiologíaRESUMEN
BACKGROUND: The International Standards for a Safe Practice of Anesthesia (ISSPA) were developed on behalf of the World Federation of Societies of Anaesthesiologists and the World Health Organization. It has been recommend as an assessment tool that allows anesthetic providers in developing countries to assess their compliance and needs. This study was performed to describe the anesthesia service in one main public hospital during an 8-month medical mission in Cambodia and evaluate its anesthetic safety issues according to the ISSPA. METHODS: We conduct a retrospective study involving 1953 patients at the Preah Ket Mealea hospital. Patient demographics, anesthetic techniques, and complications were reviewed according to the registers of the anesthetic services and questionnaires. The inadequacies in personnel, facilities, equipment, medications, and conduct of anesthesia drugs were recorded using a checklist based on the ISSPA. RESULTS: A total of 1792 patients received general and regional anesthesia in the operating room, while 161 patients receiving sedation for gastroscopy. The patients' mean age was 45.0 ± 16.6 years (range, 17-87 years). The three most common surgical procedures were abdominal (52.0%; confidence interval [CI], 49.3-54.7), orthopedic (27.6%; CI, 25.2-29.9), and urological surgery (14.7%; CI, 12.8-16.6). General anesthesia, spinal anesthesia, and brachial plexus block were performed in 54.3% (CI, 51.7-56.8), 28.2% (CI, 25.9-30.5), and 9.4% (CI, 7.9-10.9) of patients, respectively. One death occurred. Twenty-six items related to professional aspects, monitoring, and conduct of anesthesia did not meet the ISSPA-recommended standards. A lack of commonly used drugs and monitoring equipment was noted, posing major threats to the safety of anesthesia practice, especially in emergency situations. CONCLUSIONS: This study adds to the scarce literature on anesthesia practice in low- and middle-income countries such as Cambodia. Future medical assistance should help to strengthen these countries' inadequacies, allowing for the adoption of international standards for the safe practice of anesthesia.
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Anestesia/normas , Países en Desarrollo , Hospitales Públicos/organización & administración , Administración de la Seguridad/organización & administración , Administración de la Seguridad/normas , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Cambodia , Femenino , Investigación sobre Servicios de Salud , Humanos , Masculino , Misiones Médicas , Persona de Mediana Edad , Estudios Retrospectivos , Organización Mundial de la Salud , Adulto JovenRESUMEN
Diabetic neuropathic pain (DNP) is a prevalent complication in diabetes patients. Neuronal inflammation and activation of Toll-like receptor 4 (TLR4) are involved in the occurrence of DNP. However, the underlying mechanisms remain unclear. Downregulation of gamma-aminobutyric acid B (GABAB) receptor contributes to the DNP. GABAB receptor interacts with NF-κB, a downstream signaling factor of TLR4, in a neuropathic pain induced by chemotherapy. In this study, we determined the role of TLR4/Myd88/NF-κB signaling pathways coupled to GABAB receptors in the generation of DNP. Intrathecal injection of baclofen (GABAB receptor agonist), LPS-RS ultrapure (TLR4 antagonist), MIP (MyD88 antagonist), or SN50 (NF-κB inhibitor) significantly increased paw withdrawal threshold (PWT) and paw withdrawal thermal latency (PWTL) in DNP rats, while intrathecal injection of saclofen (GABAB receptor blocker) decreased PWT and PWTL in DNP rats. The expression of TLR4, Myd88, NF-κBp65, and their downstream components IL-1 and TNF-α was significantly higher in the spinal cord tissue in DNP rats compared to control rats. Following inhibition of TLR4, Myd88, and NF-κB, the expression of IL-1 and TNF-α decreased. Activation of GABAB receptors downregulated the expression of TLR4, Myd88, NF-κBp65, IL-1, and TNF-α. Blockade of GABAB receptors significantly upregulated expression of TLR4, Myd88, NF-κBp65, IL-1, and TNF-α. These data suggest that activation of the TLR4/Myd88/NF-κB signaling pathway is involved in the occurrence of DNP in rats. Activation of GABAB receptor in the spinal cord may suppress the TLR4/Myd88/NF-κB signaling pathway and alleviate the DNP.
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Neuropatías Diabéticas/metabolismo , Receptores de GABA-B/metabolismo , Asta Dorsal de la Médula Espinal/metabolismo , Receptor Toll-Like 4/metabolismo , Animales , Western Blotting , Ensayo de Inmunoadsorción Enzimática , Técnica del Anticuerpo Fluorescente , Masculino , Ratas , Ratas Sprague-Dawley , Transducción de Señal/fisiologíaRESUMEN
Propofol pretreatment before reperfusion, or propofol conditioning, has been shown to be cardioprotective, while its mechanism is unclear. The current study investigated the roles of endocannabinoid signaling in propofol cardioprotection in an in vivo model of myocardial ischemia/reperfusion (I/R) injury and in in vitro primary cardiomyocyte hypoxia/reoxygenation (H/R) injury. The results showed that propofol conditioning increased both serum and cell culture media concentrations of endocannabinoids including anandamide (AEA) and 2-arachidonoylglycerol (2-AG) detected by LC-MS/MS. The reductions of myocardial infarct size in vivo and cardiomyocyte apoptosis and death in vitro were accompanied with attenuations of oxidative injuries manifested as decreased reactive oxygen species (ROS), malonaldehyde (MDA), and MPO (myeloperoxidase) and increased superoxide dismutase (SOD) production. These effects were mimicked by either URB597, a selective endocannabinoids degradation inhibitor, or VDM11, a selective endocannabinoids reuptake inhibitor. In vivo study further validated that the cardioprotective and antioxidative effects of propofol were reversed by selective CB2 receptor antagonist AM630 but not CB1 receptor antagonist AM251. We concluded that enhancing endogenous endocannabinoid release and subsequent activation of CB2 receptor signaling represent a major mechanism whereby propofol conditioning confers antioxidative and cardioprotective effects against myocardial I/R injury.
Asunto(s)
Apoptosis/efectos de los fármacos , Propofol/farmacología , Receptor Cannabinoide CB2/metabolismo , Animales , Ácidos Araquidónicos/farmacología , Benzamidas/farmacología , Carbamatos/farmacología , Células Cultivadas , Endocannabinoides/análisis , Endocannabinoides/metabolismo , Indoles/farmacología , Masculino , Malondialdehído/sangre , Malondialdehído/metabolismo , Daño por Reperfusión Miocárdica/inducido químicamente , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Miocitos Cardíacos/citología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Pentobarbital/toxicidad , Peroxidasa/sangre , Peroxidasa/metabolismo , Propofol/uso terapéutico , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/antagonistas & inhibidores , Receptor Cannabinoide CB2/genética , Transducción de Señal/efectos de los fármacos , Superóxido Dismutasa/sangre , Superóxido Dismutasa/metabolismoRESUMEN
Propofol (2,6diisopropylphenol) exerts protective effects on alveolar epithelial type II (ATII) cells, partly through attenuating hypoxiainduced apoptosis. Autophagy is involved in the activation of apoptosis. Therefore, the present study investigated the modulating effect of propofol against autophagy in ATII cells under hypoxia. Western blot analysis was performed to detect the protein expression of the autophagy molecular marker, microtubuleassociated protein 1 light chain 3 (LC3)II, under various conditions. The effects of propofol on the accumulation of other autophagyassociated proteins and apoptosisassociated proteins were also determined using western blot analysis. The interactions between proteins were determined by coimmunoprecipitation. Apoptosis of the ATII cells was monitored using FITCconjugated AV/PI staining. Furthermore, hypoxiainducible factor 1α (HIF 1α) small interfering (si) RNA was designed to construct siHIF 1α ATII cells. The efficiency of interference was measured using reverse transcriptionquantitative polymerase chain reaction and western blot analyses. Following pretreatment with propofol, the hypoxiainduced accumulation of LC3II, HIF 1α and Bcell lymphoma2 interacting protein 3 (Bnip3) were markedly decreased, accompanied with the activation of mammalian target of rapamycin. In addition, cleavedpoly ADPribose polymerase was suppressed, and hypoxiainduced autophagic cell death was inhibited by propofol pretreatment. HIF 1α was inhibited by siHIF 1α, which simultaneously suppressed Bnip3 and LC3II under hypoxia. Taken together, propofol reduced hypoxiainduced autophagic cell death through reducing the expression of HIF 1α in ATII cells, indicating a novel strategy for modulating autophagy via propofol in hypoxic ATII cells.
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Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/patología , Autofagia , Regulación hacia Abajo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Hipoxia/metabolismo , Hipoxia/patología , Propofol/uso terapéutico , Células Epiteliales Alveolares/efectos de los fármacos , Animales , Autofagia/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Masculino , Proteínas Asociadas a Microtúbulos/metabolismo , Propofol/farmacología , ARN Interferente Pequeño/metabolismo , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
BACKGROUND: Increasing evidence suggests the potential involvement of metalloproteinase family proteins in the pathogenesis of neuropathic pain, although the underlying mechanisms remain elusive. METHODS: Using the spinal nerve ligation model, we investigated whether ADAM10 proteins participate in pain regulation. By implementing invitro methods, we produced a purified culture of satellite glial cells to study the underlying mechanisms of ADAM10 in regulating neuropathic pain. RESULTS: Results showed that the ADAM10 protein was expressed in calcitonin gene-related peptide (CGRP)-containing neurons of the dorsal root ganglia, and expression was upregulated following spinal nerve ligation surgery invivo. Intrathecal administration of GI254023X, an ADAM10 selective inhibitor, to the rats one to three days after spinal nerve ligation surgery attenuated the spinal nerve ligation-induced mechanical allodynia and thermal hyperalgesia. Intrathecal injection of ADAM10 recombinant protein simulated pain behavior in normal rats to a similar extent as those treated by spinal nerve ligation surgery. These results raised a question about the relative contribution of ADAM10 in pain regulation. Further results showed that ADAM10 might act by cleaving E-cadherin, which is mainly expressed in satellite glial cells. GI254023X reversed spinal nerve ligation-induced downregulation of E-cadherin and activation of cyclooxygenase 2 after spinal nerve ligation. ß-catenin, which creates a complex with E-cadherin in the membranes of satellite glial cells, was also downregulated by spinal nerve ligation surgery in satellite glial cells. Finally, knockdown expression of ß-catenin by lentiviral infection in purified satellite glial cells increased expression of inducible nitric oxide synthase and cyclooxygenase 2. CONCLUSION: Our findings indicate that neuron-derived ADAM10 production stimulates peripheral nerve injury-induced neuropathic pain by cleaving E-cadherin in satellite glial cells.
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Proteína ADAM10/biosíntesis , Cadherinas/metabolismo , Neuralgia/metabolismo , Neuronas/metabolismo , Células Satélites Perineuronales/metabolismo , Animales , Ganglios Espinales/metabolismo , Ligadura , Masculino , Traumatismos de los Nervios Periféricos/metabolismo , Ratas , Ratas Sprague-Dawley , Nervios EspinalesRESUMEN
BACKGROUND: Irisin is a novel exercise-induced myokine involved in the regulation of adipose browning and thermogenesis. In this study, we investigated the potential role of irisin in cerebral ischemia and determined whether irisin is involved in the neuroprotective effect of physical exercise in mice. MATERIALS AND METHODS: The middle cerebral artery occlusion (MCAO) model was used to produce cerebral ischemia in mice. First, the plasma irisin levels and changes in expression of the irisin precursor protein FNDC5 in skeletal muscle were determined post ischemic stroke. Second, the association between plasma irisin levels and the neurological deficit score, brain infarct volume, or plasma concentrations of tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1ß in mice with MCAO were evaluated. Third, the therapeutic effect of irisin on ischemic brain injury was evaluated in vivo and in vitro. Recombinant irisin was injected directly into the tail vein 30min after the MCAO operation, and then the effects of irisin treatment on brain infarct volume, neurological deficit, neuroinflammation, microglia activation, monocyte infiltration, oxidative stress and intracellular signaling pathway activation (Akt and ERK1/2) were measured. Irisin was also administered in cultured PC12 neuronal cells with oxygen and glucose deprivation (OGD). Finally, to assess the potential involvement of irisin in the neuroprotection of physical exercise, mice were exercised for 2weeks and an irisin neutralizing antibody was injected into these mice to block irisin 1h before the MCAO operation. RESULTS: The plasma irisin concentration and intramuscular FNDC5 protein expression decreased after ischemic stroke. Plasma irisin levels were negatively associated with brain infarct volume, the neurological deficit score, plasma TNF-α and plasma IL-6 concentrations. In OGD neuronal cells, irisin protected against cell injury. In mice with MCAO, irisin treatment reduced the brain infarct volume, neurological deficits, brain edema and the decline in body weight. Irisin treatment inhibited activation of Iba-1+ microglia, infiltration of MPO-1+ monocytes and expression of both TNF-α and IL-6 mRNA. Irisin significantly suppressed the levels of nitrotyrosine, superoxide anion and 4-hydroxynonenal (4-HNE) in peri-infarct brain tissues. Irisin treatment increased Akt and ERK1/2 phosphorylation, while blockade of Akt and ERK1/2 by specific inhibitors reduced the neuroprotective effects of irisin. Finally, the exercised mice injected with irisin neutralizing antibody displayed more severe neuronal injury than the exercised mice injected with control IgG. CONCLUSION: Irisin reduces ischemia-induced neuronal injury via activation of the Akt and ERK1/2 signaling pathways and contributes to the neuroprotective effect of physical exercise against cerebral ischemia, suggesting that irisin may be a factor linking metabolism and cardio-cerebrovascular diseases.
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Isquemia Encefálica/patología , Isquemia Encefálica/prevención & control , Fibronectinas/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neuronas/patología , Fármacos Neuroprotectores/farmacología , Proteína Oncogénica v-akt/efectos de los fármacos , Condicionamiento Físico Animal , Animales , Conducta Animal , Fibronectinas/metabolismo , Humanos , Infarto de la Arteria Cerebral Media/patología , Ratones , Ratones Endogámicos C57BL , Enfermedades del Sistema Nervioso/patología , Células PC12 , Ratas , Transducción de Señal/efectos de los fármacos , Accidente Cerebrovascular/prevención & controlRESUMEN
FGF10 is a member of fibroblast growth factors (FGFs). We previously showed that FGF10 protects neuron against oxygen-glucose deprivation injury in vitro; however, the effect of FGF10 in ischemic stroke in vivo is unknown. In the present study, we showed that FGF10 was mainly expressed in neurons but not astrocytes, and detected FGF10 in mouse cerebrospinal fluid. The FGF10 levels in neurons culture medium and cell lysate were much higher than those in astrocytes. FGF10 expression in brain tissue and FGF10 level in CSF were increased in mouse middle cerebral artery occlusion (MCAO) model. Administration of FGF10 into lateral cerebroventricle not only decreased MCAO-induced brain infarct volume and neurological deficit, but also reduced the number of TUNEL-positive cells and activities of Caspases. Moreover, FGF10 treatment depressed the triggered inflammatory factors (TNF-α and IL-6) and NF-κB signaling pathway, and increased phosphorylation of PI3K/Akt signaling pathway. Blockade of PI3K/Akt signaling pathway by wortmannin and Akt1/2-kinase inhibitor, partly compromised the neuroprotection of FGF10. However, blockade of PI3K/Akt signaling pathway did not impair the anti-inflammation action of FGF10. Collectively, our results demonstrate that neuron-derived FGF10 ameliorates cerebral ischemia injury via inhibiting NF-κB-dependent neuroinflammation and activating PI3K/Akt survival signaling pathway in mice.
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Isquemia Encefálica/metabolismo , Factor 10 de Crecimiento de Fibroblastos/metabolismo , FN-kappa B/metabolismo , Neuronas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Daño por Reperfusión/metabolismo , Transducción de Señal , Animales , Apoptosis/efectos de los fármacos , Isquemia Encefálica/patología , Modelos Animales de Enfermedad , Factor 10 de Crecimiento de Fibroblastos/farmacología , Inflamación/metabolismo , Inflamación/patología , Masculino , Ratones , Modelos Biológicos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Daño por Reperfusión/patología , Transducción de Señal/efectos de los fármacosRESUMEN
Fibroblast growth factors (FGFs) are a family of structurally related heparin-binding proteins with diverse biological functions. FGFs participate in mitogenesis, angiogenesis, cell proliferation, development, differentiation and cell migration. Here, we investigated the potential effect of FGF10, a member of FGFs, on neuron survival in oxygen-glucose deprivation (OGD) model. In primary cultured mouse cortical neurons upon OGD, FGF10 treatment (100 and 1000 ng/ml) attenuated the decrease of cell viability and rescued the LDH release. Tuj-1 immunocytochemistry assay showed that FGF10 promoted neuronal survival. Apoptosis assay with Annexin V+PI by flow cytometry demonstrated that FGF10 treatment reduced apoptotic cell proportion. Moreover, immunoblotting showed that FGF10 alleviated the cleaved caspase-3 upregulation caused by OGD. FGF10 treatment also depressed the OGD-induced increase of caspase-3, -8 and -9 activities. At last, we found FGF10 triggered heme oxygenase-1 (HO-1) protein expression rather than hypoxia-inducible factor-1 (HIF-1), AMP-activated protein kinase (AMPK) signaling and extracellular signal-regulated kinases 1/2 (ERK1/2) signaling. Knockdown of HO-1 by siRNA partly abolished the neuroprotection of FGF10 in OGD model. In summary, our observations provide the first evidence for the neuroprotective function of FGF10 against ischemic neuronal injury and suggest that FGF10 may be a promising agent for treatment of ischemic stroke.
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Glucemia/metabolismo , Factor 10 de Crecimiento de Fibroblastos/metabolismo , Hemo-Oxigenasa 1/metabolismo , Proteínas de la Membrana/metabolismo , Neuronas/metabolismo , Oxígeno/metabolismo , Animales , Apoptosis , Isquemia Encefálica/patología , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Corteza Cerebral/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Citometría de Flujo , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Células PC12 , ARN Interferente Pequeño/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismo , Accidente Cerebrovascular/patologíaRESUMEN
Ras association (RalGDS/AF-6) domain family member RASSF5 has been implicated in a variety of key biological processes, including cell proliferation, cell cycle regulation and apoptosis. It is believed to play an important role in tumorigenesis as a tumor suppressor in a number of malignancies. Yet, little is known concerning the function and underlying mechanisms of RASSF5 in human osteosarcoma (OS). The expression of RASSF5 was examined by immunohistochemical assay using a tissue microarray in 45 cases of OS tissues. A gain-of-function approach was used to observe the effects of lentiviral vector-mediated overexpression of RASSF5 (Lv-RASSF5) on cell growth, invasion and apoptosis, respectively, as indicated by MTT, Transwell and flow cytometry assays, and the expression levels of mammalian sterile 20-like (MST1) kinase, large tumor suppressor 1 (LATS1), proliferating cell nuclear antigen (PCNA), matrix metallopeptidase-9 (MMP-9) and p53 were detected by real-time PCR and western blot assays in OS cells (MG-63 and U-2 OS). The results indicated that the expression of RASSF5 protein was significantly downregulated in OS tissues compared to that in adjacent non-cancerous tissues (ANCT) (40.0 vs. 73.3%, P=0.002), and had a negative correlation with distant metastasis of the tumor (P=0.01). Overexpression of RASSF5 markedly suppressed cell proliferation and invasion, and induced cell apoptosis in the OS cell lines with increased expression of MST1, LATS1 and p53 and decreased expression of PCNA and MMP-9. Taken together, our findings demonstrate that RASSF5 expression is negatively correlated with distant metastasis of OS, and RASSF5 may function as a tumor suppressor in OS cells through activation of the MST1/LATS1 pathway.
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Apoptosis/genética , Neoplasias Óseas/genética , Proliferación Celular/genética , Proteínas de Unión al GTP Monoméricas/genética , Osteosarcoma/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Proteínas Reguladoras de la Apoptosis , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Línea Celular Tumoral , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Proteínas de Unión al GTP Monoméricas/metabolismo , Invasividad Neoplásica/genética , Osteosarcoma/metabolismo , Osteosarcoma/patología , Antígeno Nuclear de Célula en Proliferación/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismo , Adulto JovenRESUMEN
AIMS: Spinal cord injury (SCI) can induce excessive astrocyte activation. Hydrogen has been deemed as a novel antioxidant. We investigated whether molecular hydrogen could act as an antiastrogliosis agent during SCI and oxidative injury in experimental rats and cultured astrocytes. METHODS: Hydrogen-rich saline (HS, 8 mL/kg, i.p.) was injected every 12 h after SCI in rats. The expression of STAT3, p-STAT3, and glial fibrillary acidic protein (GFAP); the release of IL-1ß, IL-6, and TNF-α; and astrogliosis, along with the BBB score, were evaluated. Culturing astrocytes with hydrogen-rich medium, the intracellular reactive oxygen species (ROS), astrogliosis, and the release of proinflammatory cytokines were assessed after H2O2-induced injury. RESULTS: In the HS group, the expression of STAT3, p-STAT3, and GFAP and the proinflammatory cytokines were decreased in local spinal cord on postoperation day (POD) 3; on PODs 7 and 14, reactive astrogliosis was suppressed, and the locomotor function was also improved. Furthermore, hydrogen-rich medium attenuated the intracellular production of ROS (especially HOâ¢), astrogliosis, and the secretion of proinflammatory cytokines in astrocytes 12 h after H2O2-induced injury. CONCLUSIONS: Molecular hydrogen could suppress reactive astrogliosis after contusive SCI and reduce the release of proinflammatory cytokines produced by active astrocytes related to oxidative injury. Thus, molecular hydrogen is potential to be a neuroprotective agent.
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Astrocitos/fisiología , Gliosis/inducido químicamente , Hidrógeno/farmacología , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/patología , Animales , Animales Recién Nacidos , Astrocitos/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Cloruros/farmacología , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Compuestos Férricos/farmacología , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Peróxido de Hidrógeno/toxicidad , Locomoción/efectos de los fármacos , Extremidad Inferior/fisiopatología , Masculino , Ratas , Ratas Sprague-Dawley , Factores de Transcripción STAT/metabolismoRESUMEN
OBJECT: Sevoflurane and propofol are both widely used in clinical anesthesia. The aim of this study is to compare the effects of sevoflurane and propofol on right ventricular function and pulmonary circulation in patients receiving esophagectomy. METHODS: Forty adult patients undergoing an elective open-chest thoracotomy for esophagectomy were randomized to receive either propofol (n=20) or sevoflurane (n=20) as the main anesthetic agent. The study was performed in Changzheng Hospital. Hemodynamic data were recorded at specific intervals: before the surgery (T0), BIS values reaching 40 after anesthesia induction (T1), two-lung ventilation (T2), ten minutes after one-lung ventilation (T3), the end of the operation (T4) using PiCCO2 and Swan-Ganz catheter. RESULTS: CI, RVEF, RVSWI and RVEDVI were significantly smaller in propofol group than those in sevoflurane group throughout the surgery (P<0.05). However, SVRI was significantly greater in propofol group than that in sevoflurane group (P<0.05). Compared with the patients in propofol group, the patients who received sevoflurane had a greater reduction in OI and increase in Os/Ot (P<0.05). And, PVRI was significantly smaller in sevoflurane group than in propofol group (P<0.05). CONCLUSION: Anesthesia with sevoflurane preserved better right ventricular function than propofol in patients receiving esophagectomy. However, propofol improved oxygenation and shunt fraction during one-lung ventilation compared with sevoflurane anesthesia. To have the best effect, anesthesiologists can choose the two anesthetics flexibly according to the monitoring results.
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Anestésicos/efectos adversos , Esofagectomía/métodos , Éteres Metílicos/efectos adversos , Propofol/efectos adversos , Circulación Pulmonar/efectos de los fármacos , Función Ventricular Derecha/efectos de los fármacos , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , SevofluranoRESUMEN
Activated microglia exerts both beneficial and deleterious effects on neurons, but the signaling mechanism controlling these distinct responses remain unclear. We demonstrated that treatment of microglial cultures with the PAR-2 agonist, 2-Furoyl-LIGRLO-NH2, evoked early transient release of BDNF, while sustained PAR-2 stimulation evoked the delayed release of inflammatory cytokines (IL-1 ß and TNF-α) and nitric oxide. Culture medium harvested during the early phase (at 1 h) of microglial activation induced by 2-Furoyl-LIGRLO-NH2 (microglial conditioned medium, MCM) had no deleterious effects on cultured neurons, while MCM harvested during the late phase (at 72 h) promoted DNA fragmentation and apoptosis as indicated by TUNEL and annexin/PI staining. Blockade of PAR-1 during the early phase of PAR-2 stimulation enhanced BDNF release (by 11%, small but significant) while a PAR-1 agonist added during the late phase (24 h after 2-Furoyl-LIGRLO-NH2 addition) suppressed the release of cytokines and NO. The neuroprotective and neurotoxic effects of activated microglial exhibit distinct temporal profiles that are regulated by PAR-1 and PAR-2 stimulation. It may be possible to facilitate neuronal recovery and repair by appropriately timed stimulation and inhibition of microglial PAR-1 and PAR-2 receptors.
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Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Microglía/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Receptor PAR-2/fisiología , Animales , Animales Recién Nacidos , Supervivencia Celular/inmunología , Células Cultivadas , Femenino , Masculino , Oligopéptidos/farmacología , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/inmunología , Receptor PAR-2/agonistas , Factores de TiempoRESUMEN
BACKGROUND: Marked hemodynamic alteration, commonly referred to as postreperfusion syndrome (PRS), often occurs after revascularization of the donor organ during orthotopic liver transplantation (OLT) and is associated with poor outcomes. This study aimed to investigate the incidence, predictive factors and clinical outcomes of PRS in Chinese patients following OLT at a liver transplantation center in China. METHODS: Over a 5-year period, 330 consecutive patients who had undergone OLT for hepatocellular carcinoma or cirrhosis were included in this retrospective study. PRS was defined as a >30% decrease in the mean arterial pressure compared with that before revascularization for more than 1 minute during the first 5 minutes of graft reperfusion. The patients were divided into 2 groups according to the development of PRS: group 1 (patients with PRS, n=56) and group 2 (patients without PRS, n=274). The demographic characteristics, operative and postoperative courses, and outcomes of the patients were analyzed using SPSS version 18.0. RESULTS: Multivariate regression analysis showed that left ventricular diastolic dysfunction determined by echocardiography and prolonged cold ischemia time were the independent risk factors for PRS. More patients in group 1 showed postoperative renal dysfunction than those in group 2 (19.23% vs 8.4%). Moreover, patients in group 1 also had higher intraoperative (7.14% vs 0%) and postoperative mortalities (26.92% vs 12.04%). CONCLUSION: Left ventricular diastolic dysfunction and prolonged cold ischemia time contribute to a high incidence of PRS, which is associated with adverse outcomes in Chinese patients following OLT.
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Hemodinámica , Trasplante de Hígado/efectos adversos , Complicaciones Posoperatorias/etiología , Adulto , Anciano , Análisis de Varianza , Presión Sanguínea , Distribución de Chi-Cuadrado , China , Isquemia Fría/efectos adversos , Femenino , Humanos , Incidencia , Riñón/fisiopatología , Trasplante de Hígado/mortalidad , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/fisiopatología , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Disfunción Ventricular Izquierda/complicaciones , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
PURPOSE: The objective of this study was to appraise the safety profiles of HES preparations and to find out which HES preparation was the most acceptable in cardiovascular surgery through a comparison with control solutions. METHODS: Pertinent randomized controlled trials were selected through a search of Pubmed, Embase, and Cochrane Controlled Trials Register. Quantitative and qualitative analysis was carried out to evaluate blood loss, blood transfusion, renal function, complications, reoperation, and mortality. RESULTS: A total of 3,234 patients from 52 randomized controlled trials were included. HES preparations versus control solutions in blood loss: HES 130 kD vs. albumin (SMD -0.61, 95% CI -0.82, -0.40), HES 200 kD vs. albumin (SMD -0.01, 95% CI -0.29, 0.28), HES 450 kD vs. albumin (SMD 0.47, 95% CI 0.26, 0.68). When comparing control solutions with HES preparations, 50% (HES 450 kD), 40.9% (HES 200 kD), and 18.2% (HES 130 kD) of the comparisons showed more blood/blood products infusion with HES than with control solutions. A numerically lower mortality rate seemed to be related to HES preparations (2.68 vs 4.23%). No difference was found in terms of complications, renal failure, or reoperation. CONCLUSIONS: Perioperative administration of HES preparations is comparatively safe. The data appraising safety profiles of HES preparations are insufficient to make direct comparisons among themselves. As the third generation of HES preparations, HES 130 kD showed a trend toward lower blood loss and transfusion rates and is a suitable choice for cardiovascular surgery.
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Procedimientos Quirúrgicos Cardiovasculares/efectos adversos , Hemostasis Quirúrgica/métodos , Derivados de Hidroxietil Almidón/efectos adversos , Sustitutos del Plasma/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Pérdida de Sangre Quirúrgica/prevención & control , Transfusión Sanguínea , Procedimientos Quirúrgicos Cardiovasculares/mortalidad , Niño , Preescolar , Humanos , Derivados de Hidroxietil Almidón/química , Derivados de Hidroxietil Almidón/uso terapéutico , Lactante , Persona de Mediana Edad , Peso Molecular , Atención Perioperativa , Sustitutos del Plasma/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
AIM: To find out if a single dose of glutamine can relieve acute renal ischaemia-reperfusion injury in rats, to explore the role of heat shock protein in this process. METHODS: Forty-eight Sprague-Dawley rats were assigned to four groups: saline as control group; glutamine group; quercetin (heat shock protein inhibitor) plus glutamine group; and quercetin plus saline group. The renal ischaemia-reperfusion rat model was established 1 h after drug administration. Serum creatinine (CR) and blood urea nitrogen (BUN) were analyzed. The kidneys were harvested to evaluate the degree of renal injuries. Heat shock protein expression was detected by immunohistochemistry and western blot. Cell apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay and apoptosis index was calculated. RESULTS: Statistical data from CR, BUN, haematoxylin-eosin (HE) dyeing and TUNEL assay results showed that ischaemia-reperfusion injury and cell apoptosis in the glutamine group were significantly milder than those in control group (P < 0.05), while ischaemia-reperfusion injury and cell apoptosis in the quercetin plus glutamine group and quercetin plus saline group were more severe than those in the control group (P < 0.05). Statistical data from immunohistochemistry and western blot results showed that heat shock protein expression was enhanced in the glutamine group compared with that in the control group (P < 0.01), while it was weaker in the quercetin plus glutamine group and quercetin plus saline group than that in the control group (P < 0.01). CONCLUSION: Our experiment suggested that a single dose of glutamine could relieve renal ischaemia-reperfusion injury in rats in 24 h, and its mechanism may be associated with enhanced heat shock protein expression. This finding may provide a new alternative for protecting against clinical renal ischaemia-reperfusion injury.