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PURPOSE: P53 is one of the key tumor suppressors. In normal cells, p53 is maintained at low levels by the ubiquitination of the ubiquitinated ligase MDM2. In contrast, under stress conditions such as DNA damage and ischemia, the interaction between p53 and MDM2 is blocked and activated by phosphorylation and acetylation, thereby mediating the trans-activation of p53 through its target genes to regulate a variety of cellular responses. Previous studies have shown that the expression of p53 is negligible in normal myocardium, tends to increase in myocardial ischemia and is maximally induced in ischemia-reperfused myocardium, demonstrating a possible key role of p53 in the development of MIRI. In this review, we detail and summarize recent studies on the mechanism of action of p53 in MIRI and describe the therapeutic agents targeting the relevant targets to provide new strategies for the prevention and treatment of MIRI. METHODS: We collected 161 relevant papers mainly from Pubmed and Web of Science (search terms "p53" and "myocardial ischemia-reperfusion injury"). After that, we selected pathway studies related to p53 and classified them according to their contents. We eventually analyzed and summarized them. RESULTS AND CONCLUSION: In this review, we detail and summarize recent studies on the mechanism of action of p53 in MIRI and validate its status as an important intermediate affecting MIRI. On the one hand, p53 is regulated and modified by multiple factors, especially non-coding RNAs; on the other hand, p53 regulates apoptosis, programmed necrosis, autophagy, iron death and oxidative stress in MIRI through multiple pathways. More importantly, several studies have reported medications targeting p53-related therapeutic targets. These medications are expected to be effective options for the alleviation of MIRI, but further safety and clinical studies are needed to convert them into clinical applications.
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PURPOSE: Histone deacetylase 3 (HDAC3) and silent information regulator 1 (SIRT1) are histone deacetylases that regulate important metabolic pathways and play important roles in diabetes and myocardial ischemia/reperfusion (IR) injury. In this study, we explored the protective mechanism of Bmal1-regulated autophagy mediated by the HDAC3/SIRT1 pathway in myocardial IR injury of diabetic rats. METHODS AND RESULTS: Type 1 diabetes was established by administering an intraperitoneal injection of streptozotocin. After 8 weeks, the left anterior descending coronary artery was ligated for 30 min and reperfused for 120 min to establish a myocardial IR injury model in diabetic rats. H9c2 cardiomyocytes were exposed to high glucose concentration (30 mM) and hypoxia/reoxygenation (H/R) stimulation in vitro. The myocardial infarct size and levels of serum cTn-I, CK-MB, and LDH in diabetic rats subjected to myocardial IR injury were significantly higher. Upregulated HDAC3 and downregulated SIRT1 expression were observed in diabetic and IR hearts, along with a lower Bmal1 level. Autophagy was rapidly increased in the hearts of diabetic or non-diabetic rats in the IR group compared with the sham group, but significantly attenuated in the hearts of diabetic rats compared with the hearts of non-diabetic rats after IR insult. Consistent with decreased autophagy, we observed increased HDAC3 expression and decreased SIRT1 and Bmal1 levels in the myocardial tissue of diabetic rats after IR. Inhibition of HDAC3 by the inhibitor RGFP966 and activation of SIRT1 by the agonist SRT1720 could significantly attenuate myocardial IR injury in diabetic rats by restoring Bmal1-regulated autophagy. CONCLUSION: Based on these findings, the disordered HDAC3/SIRT1 circuit (upregulated HDAC3 and downregulated SIRT1 levels) plays an important role in aggravating myocardial IR injury in diabetic rats by downregulating Bmal1-mediated autophagy. Treatments targeting HDAC3/SIRT1 to activate the autophagy may represent a novel strategy to alleviate myocardial IR injury in diabetes.
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Factores de Transcripción ARNTL/metabolismo , Diabetes Mellitus Experimental , Daño por Reperfusión Miocárdica , Animales , Apoptosis , Autofagia , Diabetes Mellitus Experimental/metabolismo , Histona Desacetilasas , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Miocitos Cardíacos/metabolismo , Estrés Oxidativo , Ratas , Sirtuina 1/metabolismoRESUMEN
Intestinal ischemia-reperfusion (IIR) often occurs during and following major cardiovascular or gut surgery and causes significant organ including kidney injuries. This study was to investigate the protective effect of intestinal ischemic postconditioning (IPo) on IIR-induced acute kidney injury (AKI) and the underling cellular signaling mechanisms with focus on the Nrf2/HO-1. Adult C57BL/6J mice were subjected to IIR with or without IPo. IIR was established by clamping the superior mesenteric artery (SMA) for 45 minutes followed by 120 minutes reperfusion. Outcome measures were: (i) Intestinal and renal histopathology; (ii) Renal function; (iii) Cellular signaling changes; (iv) Oxidative stress and inflammatory responses. IPo significantly attenuated IIR-induced kidney injury. Furthermore, IPo significantly increased both nuclear Nrf2 and HO-1 expression in the kidney, upregulated autophagic flux, inhibited IIR-induced inflammation and reduced oxidative stress. The protective effect of IPo was abolished by the administration of Nrf2 inhibitor (Brusatol) or Nrf2 siRNA. Conversely, a Nrf2 activator t-BHQ has a similar protective effect to that of IPo. Our data indicate that IPo protects the kidney injury induced by IIR, which was likely mediated through the Nrf2/HO-1 cellular signaling activation.
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Lesión Renal Aguda/prevención & control , Autofagia , Hemo Oxigenasa (Desciclizante)/metabolismo , Intestinos/fisiología , Poscondicionamiento Isquémico/métodos , Factor 2 Relacionado con NF-E2/metabolismo , Daño por Reperfusión/complicaciones , Lesión Renal Aguda/etiología , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Animales , Hemo Oxigenasa (Desciclizante)/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/genética , ReperfusiónRESUMEN
PURPOSE: To assess the management and safety of epidural or general anesthesia for Cesarean delivery in parturients with coronavirus disease (COVID-19) and their newborns, and to evaluate the standardized procedures for protecting medical staff. METHODS: We retrospectively reviewed the cases of parturients diagnosed with severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection disease (COVID-19). Their epidemiologic history, chest computed tomography scans, laboratory measurements, and SARS-CoV-2 nucleic acid positivity were evaluated. We also recorded the patients' demographic and clinical characteristics, anesthesia and surgery-related data, maternal and neonatal complications, as well as the health status of the involved medical staff. RESULTS: The clinical characteristics of 17 pregnant women infected with SARS-CoV-2 were similar to those previously reported in non-pregnant adult patients. All of the 17 patients underwent Cesarean delivery with anesthesia performed according to standardized anesthesia/surgery procedures. Fourteen of the patients underwent continuous epidural anesthesia with 12 experiencing significant intraoperative hypotension. Three patients received general anesthesia with tracheal intubation because emergency surgery was needed. Three of the parturients are still recovering from their Cesarean delivery and are receiving in-hospital treatment for COVID-19. Three neonates were born prematurely. There were no deaths or serious neonatal asphyxia events. All neonatal SARS-CoV-2 nucleic acid tests were negative. No medical staff were infected throughout the patient care period. CONCLUSIONS: Both epidural and general anesthesia were safely used for Cesarean delivery in the parturients with COVID-19. Nevertheless, the incidence of hypotension during epidural anesthesia appeared excessive. Proper patient transfer, medical staff access procedures, and effective biosafety precautions are important to protect medical staff from COVID-19.
RéSUMé: OBJECTIF: Évaluer la gestion et la sécurité de l'anesthésie péridurale ou de l'anesthésie générale pour un accouchement par césarienne chez des parturientes infectées par la maladie à coronavirus 2019 (COVID-19) et pour leurs nouveau-nés, et évaluer les procédures standardisées visant la protection du personnel médical. MéTHODES: Nous avons revu de manière rétrospective les cas de parturientes ayant un diagnostic de syndrome respiratoire aigu sévère lié à l'infection (SARS-CoV-2) par le coronavirus (COVID-19). L'enquête épidémiologique, leurs examens de tomodensitométrie thoracique, les analyses de laboratoire et leur positivité pour l'acide nucléique du SARS-CoV-2 ont été évalués. Nous avons également consigné les caractéristiques démographiques et cliniques des patientes, les données liées à l'anesthésie et à la chirurgie, les complications maternelles et néonatales, ainsi que l'état de santé du personnel médical concerné. RéSULTATS: Les caractéristiques cliniques des 17 femmes enceintes infectées par le SARS-CoV-2 étaient semblables à celles précédemment rapportées chez des patientes adultes non enceintes. Les 17 patientes ont subi un accouchement par césarienne sous anesthésie effectué selon les procédures standardisées d'anesthésie et de chirurgie. Parmi les quatorze patientes ayant eu une anesthésie péridurale continue, 12 patientes ont présenté une hypotension peropératoire significative. Trois patientes ont accouché sous anesthésie générale avec intubation trachéale, car nécessitant une chirurgie d'urgence. Trois parturientes sont encore en convalescence après leur accouchement par césarienne et reçoivent un traitement à l'hôpital pour la COVID-19. Trois nouveau-nés sont nés prématurément. Il n'y a pas eu de décès ou d'événement asphyxique néonatal grave. Toutes les recherches d'acide nucléique du SARS-CoV-2 chez les nouveau-nés ont été négatives. Aucun membre du personnel médical n'a été infecté pendant la durée des soins aux patientes. CONCLUSIONS: L'anesthésie par péridurale et l'anesthésie générale ont été utilisées sans danger pour l'accouchement par césarienne de parturientes atteintes de COVID-19. Cependant, l'incidence de l'hypotension au cours de l'anesthésie péridurale a paru excessive. Un transfert approprié des patientes, les procédures d'accès du personnel médical et des précautions efficaces de biosécurité sont importants pour protéger le personnel médical contre la COVID-19.
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Anestesia Epidural , Anestesia General , Cesárea , Infecciones por Coronavirus , Control de Infecciones/métodos , Transmisión de Enfermedad Infecciosa de Paciente a Profesional/prevención & control , Pandemias , Neumonía Viral , COVID-19 , Femenino , Humanos , Recién Nacido , Embarazo , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
IPO (ischaemic post-conditioning) is a promising method of alleviating myocardial IR (ischaemia-reperfusion) injury; however, IPO-mediated cardioprotection is lost in diabetic hearts via mechanisms that remain largely unclear. We hypothesized that decreased cardiac expression of DJ-1, a positive modulator of autophagy, compromises the effectiveness of IPO-induced cardioprotection in diabetic rats. Diabetic rats subjected to myocardial IR (30 min of coronary artery occlusion followed by 120 min of reperfusion) exhibited more severe myocardial injury, less cardiac autophagy, lower DJ-1 expression and AMPK (adenosine monophosphate-activated protein kinase)/mTOR (mammalian target of rapamycin) pathway activity than non-diabetic rats. IPO significantly attenuated myocardial injury and up-regulated cardiac DJ-1 expression, AMPK/mTOR activity and autophagy in non-diabetic rats but not in diabetic rats. AAV9 (adeno-associated virus 9)-mediated cardiac DJ-1 overexpression as well as pretreatment with the autophagy inducer rapamycin restored IPO-induced cardioprotection in diabetic rats, an effect accompanied by AMPK/mTOR activation and autophagy up-regulation. Combining HPO (hypoxic post-conditioning) with DJ-1 overexpression markedly attenuated HR (hypoxia-reoxygenation) injury in H9c2 cells with high glucose (HG, 30 mM) exposure, accompanied by AMPK/mTOR signalling activation and autophagy up-regulation. The DJ-1 overexpression-mediated preservation of HPO-induced cardioprotection was completely inhibited by the AMPK inhibitor compound C (CC) and the autophagy inhibitor 3-MA (3-methyladenine). Thus, decreased cardiac DJ-1 expression, which results in impaired AMPK/mTOR signalling and decreased autophagy, could be a major mechanism underlying the loss of IPO-induced cardioprotection in diabetes.
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Autofagia/fisiología , Diabetes Mellitus Experimental/complicaciones , Poscondicionamiento Isquémico/métodos , Daño por Reperfusión Miocárdica/prevención & control , Proteína Desglicasa DJ-1/fisiología , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Autofagia/efectos de los fármacos , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Regulación de la Expresión Génica , Terapia Genética/métodos , Vectores Genéticos , Masculino , Daño por Reperfusión Miocárdica/etiología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Proteína Desglicasa DJ-1/genética , Ratas Sprague-Dawley , Transducción de Señal/fisiología , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Propofol has been found to play an important role in hepatic ischemia/reperfusion (I/R) injury with the antioxidant effects. However, the molecular mechanism of propofol in hepatic I/R injury has not been fully understood. Male Sprague-Dawley rats were randomly assigned into Sham group, hepatic I/R group, and propofol treatment group. I/R injury was attained by ischemia for 1 h and reperfusion for 2 h. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity were detected. QSG-7701 cells were cultured in hypoxia condition for 15 h and then in reoxygenation condition for 6 h to imitate hypoxia/reoxygenation (H/R) injury in vitro. Real-time RT-PCR and Western blot were performed to determine the expression of miR-133a-5p and MAPK6. Luciferase reporter assay was used to determine the regulation of miR-133a-5p on MAPK6. Propofol significantly reduced the activities of serum AST and ALT induced by hepatic I/R injury in rats. Propofol increased the level of miR-133a-5p and decreased the expression of MAPK6 in vivo and in vitro. Luciferase reporter assay showed that MAPK6 was a target of miR-133a-5p. Knockdown of miR-133a-5p abrogated the effect of propofol on the upregulation of MAPK6 induced by H/R. MAPK6 overexpression promoted the cell apoptosis induced by H/R which could be attenuated by propofol. Finally, we found that miR-133a-5p reversed the protective effect of propofol in rats with hepatic I/R injury. Propofol showed protective roles for hepatic I/R injury in vivo and H/R injury in vitro, which involved with miR-133a-5p regulating the expression of MAPK6.
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MicroARNs/metabolismo , Proteínas Quinasas Activadas por Mitógenos/genética , Propofol/uso terapéutico , Sustancias Protectoras/uso terapéutico , Daño por Reperfusión/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Secuencia de Bases , Línea Celular , Regulación de la Expresión Génica/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Hígado/efectos de los fármacos , Hígado/patología , Masculino , MicroARNs/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Oxígeno/farmacología , Propofol/farmacología , Sustancias Protectoras/farmacología , Ratas Sprague-DawleyRESUMEN
Long non-coding (lncRNA) MALAT1 can be increased by hypoxia or ischemic limbs. Also, downregulation of MALAT1 contributes to reduction of cardiomyocyte apoptosis. However, the functional involvement of MALAT1 in myocardial ischemia-reperfusion (I/R) injury has not been defined. This study investigated the functional involvement of lncRNA-MALAT1 in cardioprotective effects of fentanyl. HL-1, a cardiac muscle cell line from the AT-1 mouse atrial cardiomyocyte tumor lineage was pre-treated with fentanyl and generated cell model of hypoxia-reoxygenation (H/R). Relative expression of MALAT1, miR-145, and Bnip3 mRNA in cells was determined by quantitative real-time PCR. Cardiomyocyte H/R injury was indicated by lactate dehydrogenase (LDH) release and cell apoptosis. The results showed that fentanyl abrogates expression of responsive gene for H/R and induces downregulation of MALAT1 and Bnip3 and upregulation of miR-145. We found that miR-145/Bnip3 pathway was negatively regulated by MALAT1 in H/R-HL-1 cell with or without fentanyl treatment. Moreover, both MALAT1 overexpression and miR-145 knockdown reverse cardioprotective effects of fentanyl, as indicated by increase in LDH release and cell apoptosis. The reversal effect of MALAT1 for fentanyl is confirmed in cardiac ischemia/reperfusion (I/R) mice. In summary, lncRNA-MALAT1 is sensitive to H/R injury and abrogates cardioprotective effects of Fentanyl by negatively regulating miR-145/Bnip3 pathway.
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Cardiotónicos/uso terapéutico , Fentanilo/uso terapéutico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/genética , ARN Largo no Codificante/metabolismo , Animales , Línea Celular , Técnicas de Silenciamiento del Gen , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Fenotipo , ARN Largo no Codificante/genéticaRESUMEN
Intestinal ischemic post-conditioning (IPo) protects against lung injury induced by intestinal ischemia-reperfusion (IIR) partly through promotion of expression and function of heme oxygenase-1 (HO-1). NF-E2-related factor-2 (Nrf2) is a key transcription factor that interacts with HO-1 and regulates antioxidant defense. However, the role of Nrf2 in IPo protection of IIR-induced pulmonary injury is not completely understood. Here we show that IPo significantly attenuated IIR-induced lung injury and suppressed oxidative stress and systemic inflammatory responses. IPo also increased the expression of both Nrf2 and HO-1. Consistently, the beneficial effects of IPo were abolished by ATRA and Brusatol, potent inhibitors of Nrf2. Moreover, the Nrf2 agonist t-BHQ showed similar activity as IPo. Taken together, our data suggest that Nrf2 activity, along with HO-1, plays an important role in the protective effects of IPo against IIR-induced acute lung injury.
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Lesión Pulmonar Aguda/prevención & control , Intestinos/irrigación sanguínea , Poscondicionamiento Isquémico , Factor 2 Relacionado con NF-E2/metabolismo , Daño por Reperfusión/complicaciones , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/metabolismo , Animales , Glutatión Peroxidasa/metabolismo , Hemo-Oxigenasa 1/metabolismo , Interleucina-6/sangre , Pulmón/enzimología , Masculino , Malondialdehído/metabolismo , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Distribución Aleatoria , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/sangreRESUMEN
BACKGROUND: Patients with diabetes are prone to develop cardiac hypertrophy and more susceptible to myocardial ischemia-reperfusion (I/R) injury, which are concomitant with hyperglycemia-induced oxidative stress and impaired endothelial nitric oxide (NO) synthase (eNOS)/NO signaling. Caveolae are critical in the transduction of eNOS/NO signaling in cardiovascular system. Caveolin (Cav)-3, the cardiomyocytes-specific caveolae structural protein, is decreased in the diabetic heart in which production of reactive oxygen species are increased. We hypothesized that treatment with antioxidant N-acetylcysteine (NAC) could enhance cardiac Cav-3 expression and attenuate caveolae dysfunction and the accompanying eNOS/NO signaling abnormalities in diabetes. METHODS: Control or streptozotocin-induced diabetic rats were either untreated or treated with NAC (1.5 g/kg/day, NAC) by oral gavage for 4 weeks. Rats in subgroup were randomly assigned to receive 30 min of left anterior descending artery ligation followed by 2 h of reperfusion. Isolated rat cardiomyocytes or H9C2 cells were exposed to low glucose (LG, 5.5 mmol/L) or high glucose (HG, 25 mmol/L) for 36 h before being subjected to 4 h of hypoxia followed by 4 h of reoxygenation (H/R). RESULTS: NAC treatment ameliorated myocardial dysfunction and cardiac hypertrophy, and attenuated myocardial I/R injury and post-ischemic cardiac dysfunction in diabetic rats. NAC attenuated the reductions of NO, Cav-3 and phosphorylated eNOS and mitigated the augmentation of O2-, nitrotyrosine and 15-F2t-isoprostane in diabetic myocardium. Immunofluorescence analysis demonstrated the colocalization of Cav-3 and eNOS in isolated cardiomyocytes. Immunoprecipitation analysis revealed that diabetic conditions decreased the association of Cav-3 and eNOS in isolated cardiomyocytes, which was enhanced by treatment with NAC. Disruption of caveolae by methyl-ß-cyclodextrin or Cav-3 siRNA transfection reduced eNOS phosphorylation. NAC treatment attenuated the reductions of Cav-3 expression and eNOS phosphorylation in HG-treated cardiomyocytes or H9C2 cells. NAC treatment attenuated HG and H/R induced cell injury, which was abolished during concomitant treatment with Cav-3 siRNA or eNOS siRNA. CONCLUSIONS: Hyperglycemia-induced inhibition of eNOS activity might be consequences of caveolae dysfunction and reduced Cav-3 expression. Antioxidant NAC attenuated myocardial dysfunction and myocardial I/R injury by improving Cav-3/eNOS signaling.
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Acetilcisteína/farmacología , Antioxidantes/farmacología , Cardiomegalia/prevención & control , Caveolina 3/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Cardiomiopatías Diabéticas/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo III/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Cardiomegalia/inducido químicamente , Cardiomegalia/enzimología , Cardiomegalia/fisiopatología , Caveolas/efectos de los fármacos , Caveolas/enzimología , Caveolas/patología , Caveolina 3/genética , Hipoxia de la Célula , Línea Celular , Citoprotección , Diabetes Mellitus Experimental/inducido químicamente , Cardiomiopatías Diabéticas/inducido químicamente , Cardiomiopatías Diabéticas/enzimología , Cardiomiopatías Diabéticas/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Daño por Reperfusión Miocárdica/inducido químicamente , Daño por Reperfusión Miocárdica/enzimología , Daño por Reperfusión Miocárdica/fisiopatología , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Estrés Oxidativo/efectos de los fármacos , Fosforilación , Interferencia de ARN , Ratas Sprague-Dawley , Estreptozocina , Transfección , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
Patients with diabetes are vulnerable to MI/R (myocardial ischaemia/reperfusion) injury, but are not responsive to IPostC (ischaemic post-conditioning) which activates PI3K (phosphoinositide 3-kinase)/Akt (also known as PKB or protein kinase B) and JAK2 (Janus kinase 2)/STAT3 (signal transducer and activator of transcription 3) pathways to confer cardioprotection. We hypothesized that increased cardiac PTEN (phosphatase and tensin homologue deleted on chromosome 10), a major negative regulator of PI3K/Akt, is responsible for the loss of diabetic heart sensitivity to IPostC cardioprotecton. In STZ (streptozotocin)-induced Type 1 diabetic rats subjected to MI/R (30 min coronary occlusion and 120 min reperfusion), the post-ischaemic myocardial infarct size, CK-MB (creatine kinase-MB) and 15-F2t-isoprostane release, as well as cardiac PTEN expression were significantly higher than those in non-diabetic controls, concomitant with more severe cardiac dysfunction and lower cardiac Akt, STAT3 and GSK-3ß (glycogen synthase kinase 3ß) phosphorylation. IPostC significantly attenuated post-ischaemic infarct size, decreased PTEN expression and further increased Akt, STAT3 and GSK-3ß phosphorylation in non-diabetic, but not in diabetic rats. Application of the PTEN inhibitor BpV (bisperoxovanadium) (1.0 mg/kg) restored IPostC cardioprotection in diabetic rats. HPostC (hypoxic post-conditioning) in combination with PTEN gene knockdown, but not HPostC alone, significantly reduced H/R (hypoxia/reoxygenation) injury in cardiac H9c2 cells exposed to high glucose as was evident from reduced apoptotic cell death and JC-1 monomer in cells, accompanied by increased phosphorylation of Akt, STAT3 and GSK-3ß. PTEN inhibition/gene knockdown mediated restoration of IPostC/HPostC cardioprotection was completely reversed by the PI3K inhibitor wortmannin, and partially reversed by the JAK2 inhibitor AG490. Increased cardiac PTEN, by impairing PI3K/Akt and JAK2/STAT3 pathways, is a major mechanism that rendered diabetic hearts not responsive to post-conditioning cardioprotection.
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Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 1/complicaciones , Poscondicionamiento Isquémico/métodos , Daño por Reperfusión Miocárdica/prevención & control , Fosfohidrolasa PTEN/antagonistas & inhibidores , Animales , Apoptosis , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Técnicas de Silenciamiento del Gen/métodos , Janus Quinasa 2/fisiología , Masculino , Infarto del Miocardio/patología , Daño por Reperfusión Miocárdica/etiología , Daño por Reperfusión Miocárdica/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 3-Quinasa/fisiología , Fosforilación , Proteínas Proto-Oncogénicas c-akt/fisiología , ARN Interferente Pequeño/genética , Ratas Sprague-Dawley , Factor de Transcripción STAT3/fisiología , Transducción de Señal/fisiología , Compuestos de Vanadio/farmacología , Compuestos de Vanadio/uso terapéuticoRESUMEN
Diabetic nephropathy (DN) is one of the most common chronic complications of diabetes, which is associated with an increased oxidative stress induced by hyperglycemia and alterations in DJ-1/NF-E2-related factor-2 (Nrf2) pathway. In the present study, we investigated the role and the proper time nodes of DJ-1/Nrf2 pathway in the pathogenesis of DN. Diabetes mellitus (DM) model of rats was induced by intraperitoneal injection of streptozotocin (STZ) on male Sprague-Dawley (SD) rats. Then, the diabetic rats were divided into 4, 8 and 12 weeks groups. As early at 4 weeks of diabetes, renal histologic evaluation score, cystatin C (Cys C), ß2-microglobulin (ß2-MG) and malondialdehyde (MDA) levels were increased, and total antioxidative capacity (T-AOC) level was decreased as compared with that in the control group. The protein expressions of DJ-1, NF-E2-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1) were upregulated compared with the control group from 4 weeks and further increased with the progression of DM. The protein expressions of DJ-1, Nrf2 and HO-1 in renal tissues have good line correlations with renal histologic evaluation score, respectively. Taken together, these results suggested that the activation of DJ-1/Nrf2 pathway was involved in the pathogenesis of diabetic nephropathy in rats.
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Nefropatías Diabéticas/etiología , Factor 2 Relacionado con NF-E2/fisiología , Proteína Desglicasa DJ-1/fisiología , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
BACKGROUND: The aim of the study was to determine the median effective dose (ED50) for motor block of various concentrations of intrathecally administered plain bupivacaine. MATERIAL AND METHODS: Between 2011 and 2013, 64 patients aged ≥70 years, undergoing transurethral, or lower limb surgery with combined spinal and epidural anesthesia in a single hospital were enrolled. The patients were randomized into 3 groups to receive intrathecal 0.75% bupivacaine (Group 1), 0.375% bupivacaine (Group 2) or 0.25% bupivacaine (Group 3). Spinal anesthesia was achieved using injections of up-and-down doses of 0.75%, 0.375%, or 0.25% plain bupivacaine. The first patient in each group received 7.5 mg bupivacaine, and the testing interval was set at 0.75 mg. The efficacy of motor block in both legs was determined using a modified Bromage and a hip motor function scale. The ED50 for motor block was estimated according to the Dixon's up-and-down method. RESULTS: The ED50 for motor block of bupivacaine was 6.10 (95% CI 5.58-6.66) mg in Group 1, 6.04 (95% CI 5.82-6.28) mg in Group 2, and 5.43 (95% CI 5.19-5.67) mg in Group 3. There were significant differences in the ED50 for motor block among the groups (P=0.008). CONCLUSIONS: The ED50 doses for motor block with 3 bupivacaine concentrations were significantly different in elderly patients; the ED50 dose of 0.75% bupivacaine being significantly higher than that of 0.25% bupivacaine.
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Anestesia Raquidea/métodos , Anestésicos Locales/administración & dosificación , Bupivacaína/administración & dosificación , Bloqueo Nervioso/métodos , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inyecciones Espinales , Pierna , MasculinoRESUMEN
Inhalation anesthetic isoflurane inhibits hypoxia pulmonary vasoconstriction (HPV), while dexmedetomidine (Dex) could reduce the dose of isoflurane inhalation and potentiate HPV, but the mechanism is unclear. Inhibition of reactive oxygen species (ROS) production can favor HPV during one-lung ventilation (OLV). Similarly, nitric oxide (NO), an important endothelium-derived vasodilator in lung circulation, can decrease the regional pulmonary vascular resistance of ventilated lung and reduce intrapulmonary shunting. We hypothesized that Dex may augment HPV and improve oxygenation during OLV through inhibiting oxidative stress and increasing NO release. Patients undergoing OLV during elective thoracic surgery were randomly allocated to either isoflurane + saline (NISO, n = 24) or isoflurane + dexmedetomidine (DISO, n = 25) group. Anesthesia was maintained with intravenous remifentanil and inhalational isoflurane (1.0-2.0%), with concomitant infusion of dexmedetomidine 0.7 µgkg(-1)h(-1) in DISO and saline 0.25 mL kg(-1)h(-1) in NISO group. Hemodynamic variables or depth of anesthesia did not significantly differ between groups. Administration of Dex significantly reduced Qs/Qt and increased PaO2 after OLV, accompanied with reduced lipid peroxidation product malondialdehyde and higher levels of SOD activity as well as serum NO (all P < 0.05 DISO versus NISO). In conclusion, reducing oxidative stress and increasing NO release during OLV may represent a mechanism whereby Dex potentiates HPV.
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Dexmedetomidina/administración & dosificación , Dexmedetomidina/farmacología , Infusiones Intravenosas , Isoflurano/administración & dosificación , Ventilación Unipulmonar , Estrés Oxidativo/efectos de los fármacos , Adulto , Anestésicos por Inhalación/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Vasoconstricción/fisiologíaRESUMEN
OBJECTIVES: Heme oxygenase-1 is inducible in cardiomyocytes in response to stimuli such as oxidative stress and plays critical roles in combating cardiac hypertrophy and injury. Signal transducer and activator of transcription 3 plays a pivotal role in heme oxygenase-1-mediated protection against liver and lung injuries under oxidative stress. We hypothesized that propofol, an anesthetic with antioxidant capacity, may attenuate hyperglycemia-induced oxidative stress in cardiomyocytes via enhancing heme oxygenase-1 activation and ameliorate hyperglycemia-induced cardiac hypertrophy and apoptosis via heme oxygenase-1/signal transducer and activator of transcription 3 signaling and improve cardiac function in diabetes. DESIGN: Treatment study. SETTING: Research laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: In vivo and in vitro treatments. MEASUREMENTS AND MAIN RESULTS: At 8 weeks of streptozotocin-induced type 1 diabetes in rats, myocardial 15-F2t-isoprostane was significantly increased, accompanied by cardiomyocyte hypertrophy and apoptosis and impaired left ventricular function that was coincident with reduced heme oxygenase-1 activity and signal transducer and activator of transcription 3 activation despite an increase in heme oxygenase-1 protein expression as compared to control. Propofol infusion (900 µg/kg/min) for 45 minutes significantly improved cardiac function with concomitantly enhanced heme oxygenase-1 activity and signal transducer and activator of transcription activation. Similar to the changes seen in diabetic rat hearts, high glucose (25 mmol/L) exposure for 48 hours led to cardiomyocyte hypertrophy and apoptosis, both in primary cultured neonatal rat cardiomyocytes and in H9c2 cells compared to normal glucose (5.5 mmol/L). Hypertrophy was accompanied by increased reactive oxygen species and malondialdehyde production and caspase-3 activity. Propofol, similar to the heme oxygenase-1 inducer cobalt protoporphyrin, significantly increased cardiomyocyte heme oxygenase-1 and p-signal transducer and activator of transcription protein expression and heme oxygenase-1 activity and attenuated high-glucose-mediated cardiomyocyte hypertrophy and apoptosis and reduced reactive oxygen species and malondialdehyde production (p < 0.05). These protective effects of propofol were abolished by heme oxygenase-1 inhibition with zinc protoporphyrin and by heme oxygenase-1 or signal transducer and activator of transcription 3 gene knockdown. CONCLUSIONS: Heme oxygenase-1/signal transducer and activator of transcription 3 signaling plays a critical role in propofol-mediated amelioration of hyperglycemia-induced cardiomyocyte hypertrophy and apoptosis, whereby propofol improves cardiac function in diabetic rats.
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Factor de Transcripción Activador 3/efectos de los fármacos , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 1/complicaciones , Hemo-Oxigenasa 1/metabolismo , Propofol/farmacología , Animales , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Cardiomegalia/etiología , Diabetes Mellitus Tipo 1/inducido químicamente , Activación Enzimática , Hemo-Oxigenasa 1/efectos de los fármacos , Hiperglucemia/complicaciones , Masculino , Miocitos Cardíacos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Dexmedetomidine is a highly selective α2-adrenoreceptor agonist with sedative, analgesic and sympatholytic properties. Its cardiac protective effect cannot be ignored, notwithstanding its associated adverse drug reactions. This study aimed to investigate the effects of dexmedetomidine on L-type calcium current (ICa-L) in adult rat ventricular myocytes, and to clarify the electrophysiological mechanism of its effect on cardiomyocytes. METHODS: Single rat ventricular myocytes were obtained by enzymatic dissociation method. Myocytes were perfused with external solutions containing various concentrations of dexmedetomidine at a flow rate of 2-3 ml/min for 5 min. Whole-cell current recordings were performed using the conventional whole-cell patch-clamp technique. Besides, the effects of 1 µM yohimbine, an alpha-2 adrenergic antagonist, were given alone or in combination with 10 ng/ml dexmedetomidine. RESULTS: Dexmedetomidine inhibited the amplitude of ICa-L in a concentration-dependent manner. The current voltage curve was shifted upwards. The steady activated curves were shifted to the right and the V1/2 activation of the ICa-L were increased by dexmedetomidine at the high concentration (10 and 200 ng/ml). Dexmedetomidine did not affect the ICa-L steady-state inactivation curve, but shifted down the recovery curve. Yohimbine did not have influence on ICa-L. However, inhibition of ICa-L by dexmedetomidine at the concentration of 10 ng/ml was partially reversed by yohimbine. CONCLUSIONS: Dexmedetomidine can attenuate ICa-L in adult rat ventricular myocytes, which may contribute to its negative effects on myocardia contractility and cardiac electrophysiology. Its inhibitory effect on ICa-L is partially associated with alpha-2 adrenergic receptors. KEY WORDS: Cardiology; Dexmedetomidine; L-type calcium current; Ventricular myocytes; Whole-cell patch clamp.
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Susceptibility to myocardial ischemia-reperfusion (IR) injury in type-2 diabetes (T2DM) remains disputed, although studies have reported that ferroptosis is associated with myocardial IR injury. Nobiletin, a flavonoid isolated from citrus peels, is an antioxidant that possesses anti-inflammatory and anti-diabetic activities. However, it remains unknown whether nobiletin has any protective effects on susceptibility to myocardial IR injury during T2DM in rats via ferroptosis. To investigate the effects and underlying mechanisms of nobiletin on myocardial IR injury during T2DM, we induced myocardial IR model in rats at T2DM onset vs mature disease. We also established a high-fat high-glucose (HFHG) and hypoxia-reoxygenation (H/R) model in H9c2 cells to imitate abnormal glycolipid metabolism during T2DM. Myocardial injury, oxidative stress and ferroptosis towards myocardial IR in rats with mature T2DM but not at T2DM onset were increased. These changes were restored under treatment with ferrostain-1 or nobiletin. Both ferrostain-1 and nobiletin decreased the expression of ferroptosis-related proteins including Acyl-CoA synthetase long chain family member 4 (ACSL4) and nuclear receptor coactivator 4 (NCOA4) but not glutathione peroxidase 4 (GPX4) in rats with mature T2DM and cells with HFHG and H/R injury. Nobiletin strengthened the effect of si-ACSL4 on inhibiting ACSL4 expression, and also inhibited the effect of Erastin or oe-ACSL4 on increasing ACSL4 expression. Taken together, our data indicates that ferroptosis involves in susceptibility to myocardial IR injury in rats during T2DM. Nobiletin has therapeutic potential for alleviating myocardial IR injury associated with ACSL4- and NCOA4-related ferroptosis.
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Diabetes Mellitus Tipo 2 , Ferroptosis , Flavonas , Isquemia Miocárdica , Daño por Reperfusión Miocárdica , Daño por Reperfusión , Ratas , Animales , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Flavonas/farmacología , Flavonas/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Isquemia Miocárdica/tratamiento farmacológico , Daño por Reperfusión/metabolismoRESUMEN
Diabetes mellitus is a metabolic disease with a high prevalence worldwide, and cardiovascular complications are the leading cause of mortality in patients with diabetes. Diabetic cardiomyopathy (DCM), which is prone to heart failure with preserved ejection fraction, is defined as a cardiac dysfunction without conventional cardiac risk factors such as coronary heart disease and hypertension. Mitochondria are the centers of energy metabolism that are very important for maintaining the function of the heart. They are highly dynamic in response to environmental changes through mitochondrial dynamics. The disruption of mitochondrial dynamics is closely related to the occurrence and development of DCM. Mitochondrial dynamics are controlled by circadian clock and show oscillation rhythm. This rhythm enables mitochondria to respond to changing energy demands in different environments, but it is disordered in diabetes. In this review, we summarize the significant role of circadian clock-controlled mitochondrial dynamics in the etiology of DCM and hope to play a certain enlightening role in the treatment of DCM.
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Relojes Circadianos , Cardiomiopatías Diabéticas , Dinámicas Mitocondriales , Humanos , Mitocondrias/patología , Diabetes Mellitus , Cardiomiopatías Diabéticas/patología , AnimalesRESUMEN
BACKGROUND AND OBJECTIVE: Dizziness is a common complication of gastrointestinal endoscopy under general anesthesia. Dizziness is primarily caused by a lack of energy and blood volume following fasting and water deprivation. Hypertonic glucose solution (HGS) is an intravenous energy replenishment, that increases blood volume due to its hyperosmotic characteristics and can be directly absorbed from blood circulation. This study aimed to HGS can prevent dizziness after gastrointestinal endoscopy. METHODS: This was a double-blind, randomized, controlled study. Eligible patients were randomly allocated into two groups based on the intravenous agent administered before gastrointestinal endoscopy: Group A, saline (0.9%; 20 mL); and group B, HGS (50%; 20 mL). Overall, 840 patients were included in the statistical analysis. The scores and incidence of dizziness were assessed. RESULTS: The dizziness score were higher in group A than in group B (1.92 ± 0.08 vs. 0.92 ± 0.06; p < 0.01). The incidence of mild dizziness and moderate-to-severe dizziness was significantly lower in group B than in group A (40.10% vs. 51.78% and 3.10% vs. 19.72%, respectively; p < 0.01). The incidence and score of dizziness were significantly lower in males than in females (30.81% vs. 51.82% and 0.64 ± 0.08 vs. 1.12 ± 0.08, respectively; p < 0.01) after pretreatment with HGS. CONCLUSION: Pretreatment with HGS effectively prevents dizziness after gastrointestinal endoscopy under general anesthesia. The mechanism of action is unclear but might be related to body energy replacement and an increase in blood volume following HGS administration.
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Mareo , Solución Hipertónica de Glucosa , Masculino , Femenino , Humanos , Administración Intravenosa , Endoscopía Gastrointestinal , Anestesia General/efectos adversosRESUMEN
Intestinal ischemia reperfusion (IIR) is a serious clinical condition associated with simultaneous multiple organ dysfunction. The aim of this study was to investigate the effects of ginsenoside Rb1 on IIR induced renal injury in mice. An intestinal ischemia reperfusion mouse model was established by superior mesenteric artery (SMA) occlusion for 45 min, followed by reperfusion for 2 h. IIR induced renal injury characterized by increase of BUN, Cr and NGAL in serum, MDA levels and decrease of SOD levels in the renal tissues. Ginsenoside Rb1 (30, 60 mg/kg) given intraperitoneally before reperfusion attennuated renal injury, which was associated with decrease of BUN, Cr and NGAL in serum, MDA levels and increase of SOD levels in the renal tissues. Furthermore, the immunohistochemistry and Western blot data showed that ginsenoside Rb1 dramatically reversed IIR induced renal injury, associated with upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in renal tissues. Our data suggests that ginsenoside Rb1 attenuates acute renal injury induced by intestinal ischemia reperfusion by activating the Nrf2/ARE pathway.
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Lesión Renal Aguda/etiología , Lesión Renal Aguda/metabolismo , Ginsenósidos/farmacología , Intestinos/irrigación sanguínea , Isquemia/complicaciones , Daño por Reperfusión/complicaciones , Transducción de Señal , Lesión Renal Aguda/fisiopatología , Animales , Ginsenósidos/administración & dosificación , Hemo-Oxigenasa 1/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Masculino , Malondialdehído/metabolismo , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Superóxido Dismutasa/metabolismoRESUMEN
OBJECTIVE: To examine the effect of Shenmai Injection (SMJ) on ferroptosis during myocardial ischemia reperfusion (I/R) injury in rats and the underlying mechanism. METHODS: A total of 120 SPF-grade adult male SD rats, weighing 220-250 g were randomly divided into different groups according to a random number table. Myocardial I/R model was established by occluding the left anterior descending artery for 30 min followed by 120 min of reperfusion. SMJ was injected intraperitoneally at the onset of 120 min of reperfusion, and erastin (an agonist of ferroptosis), ferrostatin-1 (Fer-1, an inhibitor of ferroptosis) and ML385 (an inhibitor of nuclear factor erythroid-2 related factor 2 (Nrf2)) were administered intraperitoneally separately 30 min before myocardial ischemia as different pretreatments. Cardiac function before ischemia, after ischemia and after reperfusion was analysed. Pathological changes in the myocardium and the ultrastructure of cardiomyocytes were observed, and the myocardial infarction area was measured. Additionally, the concentration of Fe2+ in heart tissues and the levels of creatine kinase-MB (CK-MB), troponin I (cTnl), malondialdehyde (MDA) and superoxide dismutase (SOD) in serum were measured using assay kits, and the expressions of Nrf2, glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase long-chain family member 4 (ACSL4) were examined by Western blot. RESULTS: Compared with the sham group, I/R significantly injured heart tissues, as evidenced by the disordered, ruptured and oedematous myocardial fibres; the increases in infarct size, serum CK-MB, cTnI and MDA levels, and myocardial Fe2+ concentrations; and the decreases in SOD activity (P<0.05). These results were accompanied by ultrastructural alterations to the mitochondria, increased expression of ACSL4 and inhibited the activation of Nrf2/GPX4 signalling (P<0.05). Compared with I/R group, pretreatment with 9 mL/kg SMJ and 2 mg/kg Fer-1 significantly reduced myocardial I/R injury, Fe2+ concentrations and ACSL4 expression and attenuated mitochondrial impairment, while 14 mg/kg erastin exacerbated myocardial I/R injury (P<0.05). In addition, cardioprotection provided by 9 mL/kg SMJ was completely reversed by ML385, as evidenced by the increased myocardial infarct size, CK-MB, cTnI, MDA and Fe2+ concentrations, and the decreased SOD activity (P<0.05). CONCLUSIONS: Ferroptosis is involved in myocardial I/R injury. Pretreatment with SMJ alleviated myocardial I/R injury by activating Nrf2/GPX4 signalling-mediated ferroptosis, thereby providing a strategy for the prevention and treatment of ischemic heart diseases.