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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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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
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
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/sangreAsunto(s)
Glucemia/análisis , COVID-19/complicaciones , COVID-19/terapia , Complicaciones de la Diabetes , Diabetes Mellitus/terapia , Control Glucémico , Hiperglucemia/etiología , Adulto , Anciano , COVID-19/sangre , COVID-19/mortalidad , Comorbilidad , Complicaciones de la Diabetes/sangre , Femenino , Humanos , Hiperglucemia/terapia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Glomerular matrix accumulation is a hallmark of diabetic renal disease. Serine/threonine kinase PKC-ß1 mediates glucose-induced Akt S473 phosphorylation, RhoA activation, and transforming growth factor (TGF)-ß1 upregulation and finally leads to matrix upregulation in mesangial cells (MCs). It has been reported that glucose-induced PKC-ß1 activation is dependent on caveolin-1 and the presence of intact caveolae in MCs; however, whether activated PKC-ß1 regulates caveolin-1 expression and phosphorylation are unknown. Here, we showed that, although the caveolin-1 protein level had no significant change, the PKC-ß-specific inhibitor LY-333531 blocked caveolin-1 Y14 phosphorylation in high glucose (HG)-treated MCs and in the renal cortex of diabetic rats. The Src-specific inhibitor SU-6656 prevented the HG-induced association between PKC-ß1 and caveolin-1 and PKC-ß1 membrane translocation, whereas PKC-ß1 small interfering RNA failed to block Src activation, indicating that Src kinase is upstream of PKC-ß1 activation. Although LY-333531 blocked PKC-ß1 membrane translocation, it had no effect on the PKC-ß1/caveolin-1 association, suggesting that PKC-ß1 activation requires the interaction of caveolin-1 and PKC-ß1. PKC-ß1-mediated Akt S473 phosphorylation, RhoA activation, and fibronectin upregulation in response to HG were prevented by SU-6656 and nonphosphorylatable mutant caveolin-1 Y14A. In conclusion, Src activation by HG mediates the PKC-ß1/caveolin-1 association and PKC-ß1 activation, which assists in caveolin-1 Y14 phosphorylation by Src kinase. The downstream effects, including Akt S473 phosphorylation, RhoA activation, and fibronectin upregulation, require caveolin-1 Y14 phosphorylation. Caveolin-1 is thus an important mediator of the profibrogenic process in diabetic renal disease.
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Caveolina 1/metabolismo , Glucosa/farmacología , Células Mesangiales/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteína de Unión al GTP rhoA/metabolismo , Animales , Diabetes Mellitus Experimental/metabolismo , Masculino , Células Mesangiales/metabolismo , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiologíaRESUMEN
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, which has lasted for nearly a year, has made people deeply aware of the strong transmissibility and pathogenicity of SARS-CoV-2 since its outbreak in December 2019. By December 2020, SARS-CoV-2 had infected over 65 million people globally, resulting in more than 1 million deaths. At present, the exact animal origin of SARS-CoV-2 remains unclear and antiviral vaccines are now undergoing clinical trials. Although the social order of human life is gradually returning to normal, new confirmed cases continue to appear worldwide, and the majority of cases are sporadic due to environmental factors and lax self-protective consciousness. This article provides the latest understanding of the epidemiology and risk factors of nosocomial and community transmission of SARS-CoV-2, as well as strategies to diminish the risk of transmission. We believe that our review will help the public correctly understand and cope with SARS-CoV-2.
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OBJECTIVE: In this study, the neuroprotective mechanism of 2-arachidonoylglycerol 2-AG against non-caspase-dependent apoptosis in mice hippocampal neurons following MCAO was investigated. METHOD: One hundred and fifty healthy clean male C57BL/6 mice were randomly divided into 3 groups: sham group, model group and 2-AG treatment group, 50 mice in each group. A modified Zea Longa method was used to establish a model of middle cerebral artery occlusion (MCAO) in mice. The apoptosis rate and mitochondrial membrane potential of hippocampal nerve cells were measured by flow cytometry. The mRNA expressions of AIF, Endo G and BNIP3 in hippocampal tissues were determined by qPCR. Western blot was used to determine the protein expressions of AIF, Endo G and BNIP3 in the mitochondria of hippocampal tissue. RESULTS: The apoptosis rate of hippocampal neurons in the group treated with 2-AG was significantly lower than that of the model (P<0.01), which indicated that 2-AG could inhibit the apoptosis of hippocampal neurons induced by MCAO. However, the mitochondrial membrane potential of hippocampal neurons in the group treated with 2-AG was significantly higher than that of the model (P<0.01), indicating that 2-AG could improve the mitochondrial membrane potential of hippocampal neurons in MCAO mice. Real-time quantitative PCR (qPCR) showed that 2-AG could inhibit the gene expressions of AIF, Endo G and BNIP3 in hippocampal tissues. Western blot results showed that 2-AG could inhibit the secretions of AIF, Endo G and BNIP3 into cytoplasm in mitochondria. CONCLUSION: Endocannabinoids 2-AG had a protective effect on neurons injury, and the mechanism was possibly associated with the protection of the brain nerve cells in the hippocampus and the integrity of the mitochondrial function. Endocannabinoids 2-AG may inhibit the non-caspase-dependent apoptosis pathway, so as to exert its nerve protective effect.
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BACKGROUND: The potential mechanism of postoperative cognitive impairment is still largely unclear. The activation of NLRP3 inflammasome had been reported to be involved in neurodegenerative diseases, including postoperative cognitive change, and is closely related to mitochondrial ROS and mitophagy. Honokiol (HNK) owns multiple organic protective effects. This study is aimed at observing the neuroprotective effect of HNK in postoperative cognitive change and examining the role of HNK in the regulation of mitophagy and the relationship between these effects and NLRP3 inflammasome activation in mice induced by surgery/anesthesia. METHODS: In this study, mice were divided into several groups: control group, surgery group, surgery+HNK group, and surgery+HNK+3-methyladenine (3-MA) group. Hippocampal tissue samples were harvested and used for proinflammatory cytokines, mitochondrial ROS, and malondialdehyde (MDA) assay. The process of mitophagy and the activation of NLRP3 inflammasome were observed by Western blot, immunohistochemistry, and transmission electron microscopy. RESULTS: The results showed that HNK treatment obviously recovered the postoperative decline and enhanced the expressions of LC3-II, Beclin-1, Parkin, and PINK1 at protein levels after surgery/sevoflurane treatment, which are both an autophagy marker and a mitophagy marker. In addition, HNK attenuated mitochondrial structure damage and reduced mtROS and MDA generation, which are closely associated with NLRP3 inflammasome activation. Honokiol-mediated mitophagy inhibited the activation of NLRP3 inflammasome and neuroinflammation in the hippocampus. Using 3-MA, an autophagy inhibitor, the neuroprotective effects of HNK on mitophagy and NLRP3 inflammasome activation were eliminated. CONCLUSION: These results indicated that HNK-mediated mitophagy ameliorates postoperative cognitive impairment induced by surgery/sevoflurane. This neuroprotective effect may be involved in inhibiting the activation of NLRP3 inflammasome and suppressing inflammatory responses in the hippocampus.
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Compuestos de Bifenilo/uso terapéutico , Disfunción Cognitiva/tratamiento farmacológico , Hipocampo/metabolismo , Inflamasomas/metabolismo , Lignanos/uso terapéutico , Mitofagia/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Complicaciones Posoperatorias/tratamiento farmacológico , Sevoflurano/efectos adversos , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Compuestos de Bifenilo/farmacología , Disfunción Cognitiva/etiología , Giro Dentado/metabolismo , Giro Dentado/patología , Femenino , Hipocampo/ultraestructura , Lignanos/farmacología , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Neuronas/efectos de los fármacos , Neuronas/patología , Estrés Oxidativo/efectos de los fármacos , Complicaciones Posoperatorias/etiología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
AIMS: Increasing evidence indicates that neuroinflammatory and oxidative stress play two pivotal roles in cognitive impairment after surgery. Honokiol (HNK), as an activator of Sirtuin3 (SIRT3), has potential multiple biological functions. The aim of these experiments is to evaluate the effects of HNK on surgery/anesthesia-induced cognitive decline in mice. METHODS: Adult C57BL/6 mice received a laparotomy under sevoflurane anesthesia and HNK or SIRT3 inhibitor (3-TYP) treatment. Cognitive function and locomotor activity of mice were evaluated using fear conditioning test and open field test on postoperative 1 and 3 days. Neuronal apoptosis in CA1 and CA3 area of hippocampus was examined using TUNEL assay. And Western blot was applied to measure the expression of pro-inflammatory cytokines and SIRT3/SOD2 signaling-associated proteins in hippocampus. Meanwhile, SIRT3 positive cells were calculated by immunohistochemistry. The mitochondrial membrane potential, malondialdehyde (MDA), and mitochondrial radical oxygen species (mtROS) were detected using standard methods. RESULTS: Honokiol attenuated surgery-induced memory loss and neuronal apoptosis, decreased neuroinflammatory response, and ameliorated oxidative damage in hippocampus. Notably, surgery/anesthesia induced an obviously decrease in hippocampal SIRT3 expression, whereas the HNK increased SIRT3 expression and thus decreased the acetylation of superoxide dismutase 2 (SOD2). However, 3-TYP treatment inhibited the HNK's rescuing effects. CONCLUSIONS: These results suggested that activation of SIRT3 by honokiol may attenuate surgery/anesthesia-induced cognitive impairment in mice through regulation of oxidative stress and neuroinflammatory in hippocampus.
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Anestesia/efectos adversos , Compuestos de Bifenilo/farmacología , Disfunción Cognitiva/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Lignanos/farmacología , Complicaciones Posoperatorias/tratamiento farmacológico , Sirtuina 3/metabolismo , Anestésicos por Inhalación/efectos adversos , Anestésicos por Inhalación/farmacología , Animales , Antiinflamatorios/farmacología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Femenino , Hipocampo/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/etiología , Inflamación/metabolismo , Laparotomía , Ratones Endogámicos C57BL , Nootrópicos/farmacología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Complicaciones Posoperatorias/metabolismo , Distribución Aleatoria , Sevoflurano/efectos adversos , Sevoflurano/farmacologíaRESUMEN
MicroRNA are significant regulators of neuropathic pain development. Neuroinflammation contributes a lot to the progression of neuropathic pain. miR-381 is involved in various pathological processes. However, the role of miR-381 in neuropathic pain development remains barely understood. Therefore, in our study, we aimed to investigate the effects of miR-381 on the process of neuropathic pain progression by establishing a rat model using chronic sciatic nerve injury (CCI). Here, we observed that miR-381 was dramatically decreased in CCI rats. Up-regulation of miR-381 strongly reduced neuropathic pain behaviors including mechanical and thermal hyperalgesia. In addition, inflammatory cytokine expression, including IL-6, IL-10 and TNF-α were significantly repressed by overexpression of miR-381. High mobility group box 1 protein (HMGB1) and Chemokine CXC receptor 4 (CXCR4) participate in neuropathic pain development. In our present study, HMGB1 and CXCR4 were predicted as direct targets of miR-381 by employing bioinformatics analysis. Overexpression of miR-381 was able to restrain the expression of HMGB1 and CXCR4 greatly. The direct correlation between HMGB1 and CXCR4 and miR-381 was confirmed in our research. Furthermore, we found that HMGB1 and CXCR4 were increased in CCI rats time-dependently. Moreover, it was demonstrated that silence of HMGB1 and CXCR4 in CCI rats depressed neuropathic pain progression greatly. In conclusion, it was indicated that miR-381could inhibit neuropathic pain development through targeting HMGB1 and CXCR4.
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Proteína HMGB1/metabolismo , MicroARNs/metabolismo , Neuralgia/genética , Receptores CXCR4/metabolismo , Animales , Secuencia de Bases , Enfermedad Crónica , Modelos Animales de Enfermedad , Femenino , Silenciador del Gen , Células HEK293 , Humanos , Inflamación/genética , Inflamación/patología , MicroARNs/genética , Neuralgia/patología , Ratas Sprague-Dawley , Nervio Ciático/lesionesRESUMEN
Although the mechanism remains unclear, ischemic postconditioning (IPO) is a promising approach to combat myocardial ischemia reperfusion (IR) injury; however, it has been proven ineffective in diabetes. The present study aimed to identify whether hyperglycemiainduced AMPactivated protein kinase (AMPK) inhibition contributes to the ineffectiveness of IPO via autophagy attenuation in diabetic hearts. Diabetic and nondiabetic rats were subjected to myocardial IR and/or IPO with/without treatment with the AMPK activator A769662 and/or autophagy inhibitor 3methyladenine (3MA). Rat cardiomyocyte H9c2 cells were pretreated with A769662 and/or 3MA, and subjected to hypoxia reoxygenation (HR) or hypoxia postconditioning (HPO). The degree of injury to the myocardium/cells, oxidative stress, AMPK/mammalian target of rapamycin (mTOR) signaling and autophagy status were analyzed. In diabetic rats the myocardial infarct size, and creatine kinaseMB and malondialdehyde release, were increased compared with nondiabetic rats, concomitant with increased cardiac dysfunction and decreased cardiac superoxide dismutase activity, AMPK phosphorylation and autophagy following IR. IPO attenuated myocardial infarct size, increased AMPK phosphorylation and enhanced autophagy in nondiabetic animals. A769662 (6.0 mg/kg) restored IPO cardioprotection in diabetic rats. In vitro, HPO combined with A769662 decreased HR injury in H9c2 cells exposed to high glucose, as evidenced by decreased lactic dehydrogenase expression and oxidative stress, accompanied by increased cell viability and autophagy. The A769662mediated restoration of IPO/HPO cardioprotection was completely reversed by treatment with the autophagy inhibitor 3MA. In conclusion, AMPK inhibition, by decreasing autophagy, may be a mechanism through which diabetic hearts are rendered unresponsive to IPO cardioprotection.
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Proteínas Quinasas Activadas por AMP/metabolismo , Autofagia , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Cardiomiopatías Diabéticas , Poscondicionamiento Isquémico , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Animales , Compuestos de Bifenilo , Diabetes Mellitus Experimental/enzimología , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/enzimología , Diabetes Mellitus Tipo 1/patología , Diabetes Mellitus Tipo 1/terapia , Cardiomiopatías Diabéticas/enzimología , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/prevención & control , Activación Enzimática/efectos de los fármacos , Masculino , Pironas/farmacología , Ratas , Ratas Sprague-Dawley , Tiofenos/farmacologíaRESUMEN
Previous studies have suggested that the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway is involved in hyperglycemiainduced lung injury. The present study aimed to investigate the roles of suppressor of cytokine signaling3 (SOCS3) in the regulation of JAK2/STAT3 activation following high glucose (HG) treatment in A549 human pulmonary epithelial cells. Cell viability was evaluated using Cell Counting Kit-8 and lactate dehydrogenase assays. HGinduced inflammatory injury in A549 cells was assessed through the evaluation of interleukin6 (IL6) and tumor necrosis factorα (TNFα) levels using ELISA. The protein expression levels of SOCS3, JAK2, STAT3, phosphorylated (p)JAK2 and pSTAT3 were determined using western blot analysis. Cellular viability was significantly decreased, whereas IL6 and TNFα levels were significantly increased, following HG stimulation of A549 cells. In addition, the protein levels of SOCS3, pJAK2 and pSTAT3 were significantly increased in HGtreated cells. Treatment with the JAK2/STAT3 inhibitor tyrphostin AG490, or SOCS3 overexpression, appeared to prevent the HGinduced alterations in protein expression. Furthermore, cellular viability was enhanced, whereas the levels of proinflammatory cytokines were suppressed. These finding suggested the involvement of the SOCS3/JAK2/STAT3 signaling pathway in HGinduced responses in lung cells. Therefore, it may be hypothesized that the inhibition of the JAK2/STAT3 pathway through SOCS3 overexpression may prevent hyperglycemiainduced lung injury, and may have therapeutic potential for the treatment of patients with diabetic lung injury.
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Glucosa/metabolismo , Janus Quinasa 2/metabolismo , Pulmón/patología , Mucosa Respiratoria/patología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Proteína 3 Supresora de la Señalización de Citocinas/genética , Células A549 , Supervivencia Celular , Humanos , Hiperglucemia/complicaciones , Hiperglucemia/genética , Hiperglucemia/metabolismo , Hiperglucemia/patología , Inflamación/complicaciones , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Pulmón/citología , Pulmón/metabolismo , Lesión Pulmonar/etiología , Lesión Pulmonar/genética , Lesión Pulmonar/metabolismo , Lesión Pulmonar/patología , Mucosa Respiratoria/citología , Mucosa Respiratoria/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Regulación hacia ArribaRESUMEN
(-)-Epigallocatechin gallate (EGCG) exerts multiple beneficial effects on cardiovascular performance. In this study, we aimed to examine the effects of EGCG on diabetic cardiomyopathy during myocardial ischemia/reperfusion (I/R) injury. EGCG (100 mg/kg/day) was administered at week 6 for 2 weeks to diabetic rats following the induction of type 1 diabetes by streptozotocin (STZ). At the end of week 8, the animals were subjected to myocardial I/R injury. The EGCG-elicited structural and functional effects were analyzed. Additionally, EGCG (20 µM) was administered for 24 h to cultured cardiac H9c2 cells under hyperglycemic conditions (30 mM glucose) prior to hypoxia/reoxygenation (H/R) challenge, and its effects on oxidative stress were compared to H9c2 cells transfecteed with silent information regulator 1 (SIRT1) small interfering RNA (siRNA). In rats with STZ-induced diabetes, EGCG treatment ameliorated post-ischemic cardiac dysfunction, decreased the myocardial infarct size, apoptosis and cardiac fibrosis, and reduced the elevated lactate dehydrogenase (LDH) and malonaldehyde (MDA) levels, and attenuated oxidative stress. Furthermore, EGCG significantly reduced H/R injury in cardiac H9c2 cells exposed to high glucose as evidenced by reduced apoptotic cell death and oxidative stress. The protein expression levels of SIRT1 and manganese superoxide dismutase (MnSOD) were reduced in the diabetic rats and the H9c2 cells under hyperglycemic conditions, compared with the control rats following I/R injury and H9c2 cells under normal glucose conditions. EGCG pre-treatment significantly upregulated the levels of htese proteins in vitro and in vivo. However, treatment with EX527 and SIRT1 siRNA blocked the EGCG-mediated cardioprotective effects. Taken together, our data indicate that SIRT1 plays a critical role in the EGCG-mediated amelioration of I/R injury in diabetic rats, which suggests that EGCG may be a promising dietary supplement for the prevention of diabetic cardiomyopathy.
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Catequina/análogos & derivados , Hiperglucemia/tratamiento farmacológico , Infarto del Miocardio/tratamiento farmacológico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Cardiotónicos/farmacología , Catequina/farmacología , Diabetes Mellitus Experimental/fisiopatología , Hiperglucemia/patología , Masculino , Malondialdehído/metabolismo , Infarto del Miocardio/patología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Estrés Oxidativo/efectos de los fármacos , Ratas Sprague-Dawley , Sirtuina 1/metabolismo , Superóxido Dismutasa/metabolismoRESUMEN
Patients with diabetes are more vulnerable to renal ischemia/reperfusion (I/R) injury, which is implicated in hyperglycemia-induced oxidative stress. We previously reported that the hyperglycemia-induced inhibition of DJ-1, a novel oncogene that exhibits potent antioxidant activity, is implicated in the severity of myocardial I/R injury. In the present study, we aimed to explore the role of DJ-1 in hypoxia/reoxygenation (H/R) injury in renal cells exposed to high glucose (HG). For this purpose, NRK-52E cells were exposed to HG (30 mM) for 48 h and then exposed to hypoxia for 4 h and reoxygenation for 2 h, which significantly decreased cell viability and superoxide dismutase (SOD) activity, and increased the malondialdehyde (MDA) content, accompanied by a decrease in DJ1 protein expression. The overexpression of DJ1 by transfection with a DJ1 overexpression plasmid exerted protective effects against HG-induced H/R injury, as evidenced by increased CCK-8 levels and SOD activity, the decreased release of lactate dehydrogenase (LDH) and the decreased MDA content, and increased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO1) expression. Similar effects were observed following treatment with the antioxidant, N-acetylcysteine. These results suggest that the overexpression of DJ1 reduces oxidative stress and attenuates H/R injury in NRK-52E cells exposed to HG.
Asunto(s)
Células Epiteliales/efectos de los fármacos , Glucosa/farmacología , Estrés Oxidativo/efectos de los fármacos , Proteína Desglicasa DJ-1/metabolismo , Animales , Antioxidantes/farmacología , Western Blotting , Hipoxia de la Célula , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cistina/análogos & derivados , Cistina/farmacología , Relación Dosis-Respuesta a Droga , Células Epiteliales/metabolismo , Hemo-Oxigenasa 1/metabolismo , Túbulos Renales Proximales/citología , Malondialdehído/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Oxígeno/farmacología , Proteína Desglicasa DJ-1/genética , Ratas , Superóxido Dismutasa/metabolismo , Factores de Tiempo , TransfecciónRESUMEN
Ischemia postconditioning (IpostC) is an effective way to alleviate ischemia and reperfusion injury; however, the protective effects seem to be impaired in candidates with diabetes mellitus. To gain deep insight into this phenomenon, we explored the role of DJ-1, a novel oncogene, that may exhibit powerful antioxidant capacity in postconditioning cardioprotection in a rat model of myocardial ischemia reperfusion injury. Compared with normal group, cardiac DJ-1 was downregulated in diabetes. Larger postischemic infarct size as well as exaggeration of oxidative stress was observed, while IpostC reversed the above changes in normal but not in diabetic rats. DJ-1 was increased after ischemia and postconditioning contributed to a further elevation; however, no alteration of DJ-1 was documented in all subgroups of diabetic rats. Alteration of the cardioprotective PI3K/Akt signaling proteins may be responsible for the ineffectiveness of postconditioning in diabetes. There is a positive correlation relationship between p-Akt and DJ-1 but a negative correlation between infarct size and DJ-1, which may partially explain the interaction of DJ-1 and IpostC cardioprotection. Our result indicates a beneficial role of DJ-1 in myocardial ischemia reperfusion. Downregulation of cardiac DJ-1 may be responsible for the compromised diabetic heart responsiveness to IpostC cardioprotection.
Asunto(s)
Cardiotónicos/metabolismo , Hiperglucemia/complicaciones , Poscondicionamiento Isquémico , Proteínas Asociadas a Microtúbulos/metabolismo , Animales , Glucemia/metabolismo , Peso Corporal , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/patología , Hiperglucemia/sangre , Hiperglucemia/metabolismo , Hiperglucemia/patología , Modelos Lineales , Masculino , Infarto del Miocardio/sangre , Infarto del Miocardio/complicaciones , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Fosforilación , Proteína Desglicasa DJ-1 , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Transducción de SeñalRESUMEN
Ginsenoside Rb1 (RB1), the most clinically effective constituent of ginseng, possesses a variety of biological activities. The objectives of this study were to investigate the protective effects of RB1 and its underlying mechanism on renal injury induced by intestinal ischemia-reperfusion (IIR) in mice. RB1 was administered prior to inducing IIR achieved by occluding the superior mesenteric artery for 45 min followed by 120 min of reperfusion. All-trans-retinoic acid (ATRA) was used as an inhibitor of NF-E2-related factor-2 (Nrf2) signaling. Adult male C57BL/6J mice were randomly divided into six groups: (1) sham group, (2) IIR group, (3) RB1 group, (4) sham + ATRA group, (5) IIR + ATRA group, and (6) RB1 + ATRA group. Intestinal histology and pathological injury score were observed. Intestinal mucosal injury was also evaluated by measuring serum diamine oxidase (DAO). Renal injury induced by IIR was characterized by increased levels of histological severity score, blood urea nitrogen (BUN), serum creatinine (Scr) and neutrophil gelatinase-associated lipocalin (NGAL), which was accompanied with elevated renal TUNEL-positive cells and the Bcl-2/Bax expression ratio. RB1 significantly reduced renal injury and apoptosis as compared with IIR group, which was reversed by ATRA treatment. Immunohistochemistry and Western blot analysis demonstrated that RB1 significantly upregulated the protein expression of heme oxygenase-1 (HO-1) and Nrf2, which were attenuated by ATRA treatment. Taken together, these results suggest that the protective effects of RB1 pretreatment against renal injury induced by IIR are associated with activation of the Nrf2/ anti-oxidant response element (ARE) pathway.