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El precondicionamiento isquémico remoto es una manera eficaz de disminuir el daño por isquemia y reperfusión en el corazón y otros órganos como cerebro o riñón, en modelos experimentales. Este consiste en realizar entre 3 y 5 ciclos de 5 minutos de isquemia seguidos del mismo tiempo de reperfusión, en un tejido alejado del que se quiere proteger, normalmente una extremidad. Estudios preclínicos en animales indican que la isquemia precondicionante inicia señales nerviosas y humorales en el tejido isquémico remoto, que en el corazón activan mecanismos de protección. La señal nerviosa se origina en fibras sensoriales que a nivel cerebral producen una activación del sistema parasimpático. El nervio vago activa ganglios cardíacos intrínsecos del corazón lo que induce protección. Además, desde el tejido isquémico se liberan a la circulación diferentes mediadores que viajan en forma libre o en vesículas lipídicas (exosomas) que inician vías de señalización protectoras en el corazón. A pesar del éxito del precondicionamiento isquémico remoto en animales de experimentación, su aplicación en seres humanos no ha tenido resultados claros. Esta discrepancia puede deberse a una diversidad de factores tales como la edad, la existencia de otras patologías, uso de fármacos u otros tratamientos que afectan la respuesta de los pacientes. Se requiere un mayor conocimiento de las bases moleculares de este mecanismo de protección para que su aplicación en clínica sea exitosa.
In experimental models, remote ischemic preconditioning effectively decreases ischemia reperfusion injury to the heart and other organs such as the brain or kidney. It consists of 3 to 5 cycles of 5 minutes of ischemia followed by 5 minutes of reperfusion, in a remote tissue, usually a limb. Preclinical studies in animals indicate that preconditioning ischemia initiates neural and humoral signals in the remote ischemic tissue, which activate protective mechanisms in the heart. The nervous signal originates in sensory fibers that activate the parasympathetic system in the brain. The vagus nerve activates the intrinsic cardiac ganglia of the heart, leading to protection from ischemic injury. Furthermore, mediators are released from the ischemic tissue into the circulation that travels freely or in lipid vesicles (exosomes) to the heart where they initiate protective signaling pathways. Despite the success of remote ischemic preconditioning in experimental animals, its application in humans has not produced clear results. This discrepancy may be due to a variety of factors such as age, the existence of other pathologic processes, or the use of drugs or other treatments that affect the patient´s response. An increased knowledge of the molecular bases of this protective mechanism is required for its clinical application to be successful.
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Abstract Astrocytes are the most abundant cell subtypes in the central nervous system. Previous studies believed that astrocytes are supporting cells in the brain, which only provide nutrients for neurons. However, recent studies have found that astrocytes have more crucial and complex functions in the brain, such as neurogenesis, phagocytosis, and ischemic tolerance. After an ischemic stroke, the activated astrocytes can exert neuroprotective or neurotoxic effects through a variety of pathways. In this review, we will discuss the neuroprotective mechanisms of astrocytes in cerebral ischemia, and mainly focus on reactive astrocytosis or glial scar, neurogenesis, phagocytosis, and cerebral ischemic tolerance, for providing new strategies for the clinical treatment of stroke.
Resumo Os astrócitos são os subtipos de células mais abundantes no sistema nervoso central. Estudos anteriores acreditavam que os astrócitos são células de suporte no cérebro, que apenas fornecem nutrientes para os neurônios. No entanto, estudos recentes descobriram que os astrócitos têm funções mais cruciais e complexas no cérebro, como neurogênese, fagocitose e tolerância isquêmica. Após um acidente vascular cerebral isquêmico, os astrócitos ativados podem exercer efeitos neuroprotetores ou neurotóxicos através de uma variedade de vias. Nesta revisão, discutiremos os mecanismos neuroprotetores dos astrócitos na isquemia cerebral, e focaremos principalmente na astrocitose reativa ou cicatriz glial, neurogênese, fagocitose e tolerância isquêmica cerebral, para fornecer novas estratégias para o tratamento clínico do acidente vascular cerebral.
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Objective:To explore the possible mechanisms of remote ischemic preconditioning (RIPC) combined with melatonin (MT) against cerebral ischemia-reperfusion injury and to evaluate the value of multimodal MRI.Methods:From December 2021 to December 2022, fifty SPF-grade male SD rats were selected and divided into sham surgery group ( n=10), middle cerebral artery occlusion model group ( n=10), melatonin (MT) group ( n=10), remote ischemic preconditioning (RIPC) group ( n=10) and MT+RIPC group ( n=10). Neurological function scoring and multimodal MRI examinations, including T 2 fluid-attenuated inversion recovery (FLAIR) imaging, diffusion-weighted imaging (DWI), and arterial spin labeling (ASL) imaging, were performed on rats after surgery. After the scans, the rats were euthanized. The brain tissues of 3 rats in each group were randomly selected for HE staining and immunohistochemical staining to observe the pathological morphology of brain tissues and to validate the expression of nuclear factor-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). The remaining 6 rats were used for enzyme-linked immunosorbent assay to detect levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in brain infarction tissues. ANOVA test or Kruskal-Wallis H test was performed to compare the differences between groups. Results:There were statistically significant differences in neurological function scores and brain infarct volumes among the five groups ( P<0.001). Compared with the sham surgery group, the rats′ neurological function scores and brain infarct volumes were increased in the model group, RIPC group, MT group, and MT+RIPC group ( P<0.05); While compared with the model group, the rats′ neurological function scores and brain infarct volumes were decreased in the RIPC group, MT group, and MT+RIPC group ( P<0.05). MRI showed that abnormal signals were observed on the lesion hemisphere on the right side in rats of the four groups except for the sham surgery group. The lesions showed high signal on T 2 FLAIR and DWI, low signal on apparent diffusion coefficient map, and low perfusion on cerebral blood flow map. Pathological examination showed neuronal nuclear shrinkage in the necrotic area of the brain tissue in the model group, with surrounding neurons exhibiting edema and degeneration. In the RIPC and MT groups, edema and degeneration of neural cells around the infarction area were reduced, while the MT+RIPC group showed primarily neuronal edema with overall structural preservation. The range of Nrf2 and HO-1 protein positivity was significantly increased in the MT+RIPC group compared with the model group. The overall differences in IL-1β, TNF-α and IL-6 levels of 5 groups were statistically significant ( P<0.05), in which IL-1β, TNF-α and IL-6 levels in the model group, RIPC group, MT group, and MT+RIPC group increased compared with the sham-operated group ( P<0.05), and IL-1β, TNF-α, and IL-6 levels decreased in the RIPC group, MT group, and MT+RIPC group compared with the model group ( P<0.05). Conclusion:RIPC+MT exerts antioxidant effects through Nrf2/HO-1 pathway and also exhibits anti-inflammatory properties by reducing levels of IL-1β, IL-6, and TNF-α, thereby alleviating brain edema and neuronal damage, reducing infarct volume and improving neurological deficits in rats with cerebral artery occlusion. The multimodal MRI evaluation demonstrates the value of RIPC+MT in protecting against cerebral ischemia-reperfusion injury.
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AIM: To explore whether free radicals participate in cerebral ischemic tolerance and the up-regula-tion of p38 MAPK and ERK signaling pathways in rats induced by limb ischemic preconditioning (LIP). METHODS: A total of 128 Wistar rats with permanent occlusion of bilateral vertebral arteries were randomly divided into sham group (n=16), cerebral ischemia (CI) group (n=16), LIP+CI group (n=16), DMTU (a free radical scavenger)+LIP+CI group (n=64) and DMTU+sham group (n=16). Six rats in each group were used to observe the delayed neuronal death (DND) in hippocampal CA1 region by thionin staining at 7 d after the end of operation. Other 10 rats in each group were used to de-tect the expression of p38 MAPK and ERK in hippocampal CA1 region by immunohistochemistry and Western blot. RE-SULTS: Lethal CI resulted in obvious DND in hippocampal CA1 region. However, LIP reversed the above injurious changes, represented by the decrease in histological grade and the increase in neuronal density compared with CI group (P<0. 01). Moreover, LIP significantly up-regulated the expression of p38 MAPK and ERK in hippocampal CA1 region com-pared with CI group (P<0. 01). Administration of free radical scavenger DMTU via femoral vein before LIP partially re-versed the neuroprotective effect of LIP, and blocked the up-regulation of p38 MAPK and ERK expression in hippocampal CA1 region in rats compared with LIP+CI group (P<0. 01). CONCLUSION: Free radicals are involved in the neuropro-tection and up-regulation of p38 MAPK and ERK expression induced by LIP in rats.
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@#Objective To investigate the effect of simvastatin and mechanical pretreatment on intimal hyperplasia of venous graft and its mechanism. Methods Twelve New Zealand rabbits were selected and randomly divided into 4 groups: a blank control group, a simvastatin topical treatment group, a mechanical precondition group and a combined group (n=3 in each group). Ultrasound was used to evaluate the changes of graft wall and blood flow velocity in the graft, and pathological section was used to evaluate the intimal hyperplasia. Human umbilical cord endodermal cells were cultured in vitro. A simvastatin group and a solvent control group were set to detect YAP phosphorylation, downstream target gene expression and cell proliferation. Results Vascular ultrasound showed that except the simvastatin topical treatment group, the flow velocity in vein grafts in the other three groups significantly increased 21 days after surgery compared with 7 days after surgery (P<0.01). Pathological sections showed that the thickness of new intima in the simvastatin topical treatment group, mechanical precondition group, combined group and blank control group were 45.56±4.11 μm, 201.28±16.71 μm, 143.57±7.82 μm, 249.45±13.33 μm, respectively, and there were statistical differences compared with the blank control group (P<0.05). In vitro results showed that compared with the solvent control group, cell death was observed in high concentration simvastatin (5 mmol/L) group, cell proliferation was inhibited in low concentration simvastatin (2.5 mmol/L) group (P<0.05), the expression of YAP protein in the simvastatin group was unchanged, but the expression of phosphorylated YAP protein significantly increased (P<0.05), and the expression of downstream target gene ccn1 was down-regulated (P<0.001). Conclusion Intravascular local application of simvastatin and mechanical preconditioning alone or in combination can inhibit intimal hyperplasia of venous graft. High concentration of simvastatin has cytotoxicity, while low concentration of simvastatin has inhibitory effect on cell proliferation. Simvastatin can inhibit the formation of new intima by inhibiting the entry of YAP into the nucleus and reducing the transcription of cell proliferation-related target gene ccn1.
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Objective To investigate the application effect of remote ischemic preconditioning (RIPC) combined with controlled low central venous pressure (CLCVP) in hepatectomy. Methods A total of 80 patients who underwent elective partial hepatectomy in Yougchuan Hospital Affiliated to Chongqing Medical University from May 2021 to April 2022 were enrolled and divided into control group (group C), CLCVP group (group L), RIPC group (group R), and RIPC+CLCVP group (group RL) using a random number table, with 20 patients in each group. The patients in group L received CLCVP, those in group R received RIPC, and those in group RL received both CLCVP and RIPC. The patients were compared in terms of perioperative general status and the levels of tumor necrosis factor-α (TNFα), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin on preoperative day 1(D0), postoperative day 1(D1), postoperative day 3(D3), postoperative day 5(D5), and postoperative day 7(D7). A one-way analysis of variance or a repeated measures analysis of variance was used for comparison of normally distributed continuous data between groups, and the Kruskal-Wallis H test was used for comparison of continuous data with skewed distribution between groups; the chi-square test was used for comparison of categorical data. Results Compared with group R, group RL had a significantly shorter time of operation ( H =14.278, P =0.015), a significantly lower total infusion volume ( H =24.175, P =0.001), and a significantly lower estimated blood loss ( H =45.625, P < 0.001). Group and time factors had significant interaction effects on TNFα, ALT, and AST in the four groups ( P < 0.001; P =0.010; P =0.012). Group RL had a significantly lower level of TNFα than group L on D1( P < 0.001) and D3( P < 0.001). Group RL had a significantly lower level of ALT than group L on D1( P =0.008) and D7( P < 0.001). Conclusion For patients undergoing hepatectomy, RIPC combined with CLCVP can effectively reduce intraoperative blood loss, provide a clear surgical field, and shorten the time of operation; meanwhile, it can also inhibit inflammatory response by reducing TNFα, but it cannot effectively alleviate hepatic ischemia-reperfusion injury after hepatectomy under the context of CLCVP.
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Ischemic preconditioning (IPC) is a potential intervention known to protect the heart against ischemia/reperfusion injury, but its role in the no-reflow phenomenon that follows reperfusion is unclear. Dihydrotanshinone I (DT) is a natural compound and this study illustrates its role in cardiac ischemic injury from the aspect of IPC. Pretreatment with DT induced modest ROS production and protected cardiomyocytes against oxygen and glucose deprivation (OGD), but the protection was prevented by a ROS scavenger. In addition, DT administration protected the heart against isoprenaline challenge. Mechanistically, PKM2 reacted to transient ROS via oxidization at Cys423/Cys424, leading to glutathionylation and nuclear translocation in dimer form. In the nucleus, PKM2 served as a co-factor to promote HIF-1α-dependent gene induction, contributing to adaptive responses. In mice subjected to permanent coronary ligation, cardiac-specific knockdown of Pkm2 blocked DT-mediated preconditioning protection, which was rescued by overexpression of wild-type Pkm2, rather than Cys423/424-mutated Pkm2. In conclusion, PKM2 is sensitive to oxidation, and subsequent glutathionylation promotes its nuclear translocation. Although IPC has been viewed as a protective means against reperfusion injury, our study reveals its potential role in protection of the heart from no-reflow ischemia.
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Objective:To observe the effects of electroacupuncture preconditioning on the autophagy-related pathway protein kinase B (Akt)/mammalian target of rapamycin (mTOR) in myocardial tissue of rats with myocardial ischemia reperfusion injury (MIRI); To investigate the protective mechanism of "Neiguan"(PC 6) on myocardial injury.Methods:Totally 48 SD rats were randomly divided into blank group, sham-operation group, model group and Neiguan group ( n=12 in each group). The Neiguan group was applied to bilateral "Neiguan"(PC 6) by electroacupuncture for 30 min, once daily for consecutive 7 days before model replication. Except in the blank group, the MIRI model was established by ligation of the descending anterior branch of the left coronary artery in the rest groups after the intervention. The histomorphological changes in the myocardium of the rats were observed by HE staining, and the expression levels of Akt, phosphorylated Akt (p-Akt), mTOR and phosphorylated mTOR (p-mTOR) in the myocardium were measured by protein immunoblotting. The ratio of p-Akt/Akt and p-mTOR/mTOR was calculated. Results:In the blank group, the myocardial fibres were arranged regularly and neatly, and no inflammatory cell infiltration or haemorrhage was seen in the interstitium; in the sham-operation group, the arrangement of myocardial fibers was slightly irregular, no rupture was found, and a small amount of myocardial fiber gap was slightly enlarged; in the model group, the distribution of myocardial fibers was disordered, hypertrophic cardiomyocytes increased, some mitochondria were red and swollen or the outer membrane was ruptured, and inflammatory infiltration and hemorrhage were seen in the interstitium; the extent of myocardial lesions in the Neiguan group was less than that in the model group, with a small amount of interstitial hemorrhage and inflammatory cell infiltration. There was no statistical significance in the levels of Akt and mTOR in the myocardial tissues of the rats in each group ( P>0.05); compared with the sham-operation group, the levels of p-Akt, p-mTOR and p-Akt/Akt, p-mTOR/mTOR in the model group decreased ( P<0.01); compared with the model group, the levels of p-Akt, p-mTOR and p-Akt/Akt, p-mTOR/mTOR in the Neiguan group increased ( P<0.01). Conclusion:Electroacupuncture preconditioning may inhibit excessive autophagy by activating the Akt/mTOR pathway in cardiomyocytes of MIRI rats, thereby exerting a protective effect on the myocardium.
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ABSTRACT Background: The role of remote ischemic preconditioning (RIPC) in preventing the development of contrast-induced nephropathy (CIN) and whether there is a difference between the results of applications of RIPC to the upper or lower extremities has not been adequately demonstrated. Methods: We included the patients who underwent coronary angiography due to stable angina pectoris in this single center, randomized, pilot study. We randomly enrolled a total of 168 patients in one of three groups (60 patients in the upper limb RIPC group, 58 patients in the lower limb RIPC group, and 50 patients in the control group). Results: According to the Acute Kidney Injury Network (AKIN), CIN did not develop in any RIPC patients and developed in 6% of controls (OR: 3.511, 95% CI: 2.757-4.471, p=0.025). According to the European Society of Urogenital Radiology (ESUR) guidelines, CIN developed in 1.7% of RIPC patients and 8% of controls (p=0.065). It was found that creatinine levels increased in the control group and decreased in the RIPC groups (baseline: 0.81±0.19mg/dL and 0.86±0.25mg/dL and control: 0.76±0.17mg/dL and 0.91±0.36mg/ dL, p <0.001). When the upper and lower limb RIPC results were compared, there was no statistically significant difference in the incidence of CIN. In multivariate analyses we found out that baseline eGFR, baseline mean blood pressure, contrast agent volume, and RIPC were independently associated with the development of CIN. Conclusions: RIPC is a practically useful method in preventing CIN in patients undergoing coronary angiography. Upper or lower-limb RIPC applications seem to have a similar effect.
RESUMEN No se ha demostrado adecuadamente el papel del preacondicionamiento isquémico remoto (RIPC) en la prevención del desarrollo de nefropatía inducida por contraste (NIC) y si existe una diferencia entre los resultados de las aplicaciones de RIPC en las extremidades superiores o inferiores. Se incluyó a los pacientes sometidos a coronariografía por angina de pecho estable en este estudio piloto, aleatorizado, unicéntrico. Inscribimos al azar a un total de 168 pacientes en uno de los tres grupos (60 pacientes en el grupo de RIPC de miembros superiores, 58 pacientes en el grupo de RIPC de miembros inferiores, 50 pacientes en el grupo de control). De acuerdo con la Acute Kidney Injury Network (AKIN), NIC no se desarrolló en ningún paciente con RIPC y se desarrolló en el 6% de los controles (OR: 3,511, IC del 95%: 2,757-4,471, p = 0,025). Según las directrices de la Sociedad Europea de Radiología Urogenital (ESUR), la NIC se desarrolló en el 1,7% de los pacientes con RIPC y en el 8% de los controles (p = 0,065). Se encontró que los niveles de creatinina aumentaron en el grupo de control y disminuyeron en los grupos de RIPC (línea de base: 0,81 ± 0,19 mg / dL y 0,86 ± 0,25 mg / dL y control: 0,76 ± 0,17 mg / dL y 0,91 ± 0,36 mg / dL, p <0,001). Cuando se compararon los resultados de RIPC de miembros superiores e inferiores, no hubo diferencias estadísticamente significativas en la incidencia de NIC. En análisis multivariado descubrimos que la TFGe basal, la presión arterial media basal, el volumen del agente de contraste y la RIPC se asociaron de forma independiente con el desarrollo de NIC. La RIPC es un método prácticamente útil en la prevención de NIC en pacientes sometidos a coronariografía. Las aplicaciones de RIPC de miembros superiores o inferiores parecen tener un efecto similar.
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Objective:To evaluate the effect of melatonin preconditioning on hepatic ischemia-reperfusion (I/R) injury in rats with non-alcoholic fatty liver disease (NAFLD).Methods:Forty-eight SPF male Sprague-Dawley rats, aged 10-12 weeks, weighing 200-230 g, were divided into 4 groups ( n=12 each) using a random number table method: control group (Con group), NAFLD group, NAFLD + hepatic I/R group (NAFLD+ HIR group), and NAFLD + hepatic I/R + melatonin treatment group (NAFLD+ HIR+ MT group). The NAFLD model was developed by a high-fat and high-glucose diet (10% glucose, 10% fat) for 8 consecutive weeks in NAFLD, NAFLD+ HIR and NAFLD+ HIR+ M groups, and rats were fed with common chow and freely drank water in the other groups.Melatonin 10 mg/kg was given intragastrically daily for 2 consecutive weeks before developing the model in group NAFLD+ HIR+ MT.The model of liver I/R injury was developed by clipping the hepatic artery and portal vein for 20 min, opening for 5 min, and re-clamping for 20 min followed by restoration of perfusion.Blood samples from inferior vena cava were collected and liver tissues were obtained at 6 h of reperfusion to detect serum levels of insulin, blood glucose, free fatty acid (FFA), triglyceride (TG), alanine aminotransferase (ALT), aspartate amino transferase (AST) and ferritin, and insulin resistance index was calculated.The levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), reactive oxygen species (ROS) and Fe 2+ in liver tissues were detected by enzyme-linked immunosorbent assay, the pathological changes of liver tissues were examined with a light microscope after hematoxylin-eosin staining.The expression of nuclear factor E2-related factor 2 (Nrf2), lysophosphatidylcholine acyltransferase 3 (LPCAT3), long-chain fatty acyl-CoA synthase 4 (ACSL4) and glutathione peptide peroxidase 4 (GPX4) was detected by Western blot. Results:Compared with Con group, the levels of serum FFA, TG, ALT, AST and ferritin and insulin resistance index were significantly increased, the levels of ROS and Fe 2+ in liver tissues were increased, the levels of GSH-Px and SOD were decreased, the expression of ACSL4 and LPCAT3 was up-regulated, and the expression of Nrf2 and GPX4 was down-regulated in NAFLD group ( P<0.05). Compared with NAFLD group, the serum levels of FFA, TG, ALT, AST and ferritin and insulin resistance index were significantly increased, the levels of ROS and Fe 2+ were decreased, the levels of GSH-Px and SOD were increased, the expression of ACSL4 and LPCAT3 was up-regulated, and the expression of Nrf2 and GPX4 was down-regulated in NAFLD+ HIR group ( P<0.05). Compared with NAFLD+ HIR group, the serum levels of FFA, TG, ALT, AST and ferritin and insulin resistance index were significantly increased, the levels of ROS and Fe 2+ were decreased, the levels of GSH-Px and SOD were increased, the expression of ACSL4 and LPCAT3 was down-regulated, and the expression of Nrf2 and GPX4 was up-regulated in NAFLD+ HIR+ MT group ( P<0.05). Conclusions:Melatonin preconditioning can alleviate hepatic I/R injury in rats with NAFLD, and the mechanism may be related to activation of Nrf2 signaling pathway, reduction of lipid peroxidation and inhibition of ferroptosis.
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Objective:To investigate the role of Caveolin (Cav-3)/extracellular signal-regulated kinase (ERK) signaling pathway in reduction of myocardial ischemia-reperfusion (I/R) injury by morphine preconditioning in rats with chronic heart failure.Methods:Clean-grade healthy adult male Sprague-Dawley rats, weighing 200-250 g, were used in this study.Chronic heart failure was induced by ligating the left anterior descending coronary artery for 6 weeks.Thirty-six Langendorff-perfused hearts with chronic heart failure were divided into 4 groups ( n=9 each) by a random number table method: myocardial I/R group (group IR), morphine preconditioning group (group MP), morphine preconditioning plus methyl-β-cyclodextrin group (group MP+ MβCD), and methyl-β-cyclodextrin group (group MβCD). Global myocardial I/R was induced by 30 min ischemia followed by 120 min reperfusion.In group MP, after 15 min of equilibration, hearts were subjected to 3 cycles of 5 min perfusion with K-H solution containing 1 μmol/L morphine for preconditioning followed by 5 min perfusion with K-H solution, 30 min in total, and after the end of treatment, hearts were subjected to 30 min ischemia followed by 120 min reperfusion.In group MP+ MβCD, hearts were perfused with K-H solution containing 200 μmol/L methyl-β-cyclodextrin at 10 min before preconditioning with morphine, and the other treatments were similar to those previously described in group MP.In group MβCD, hearts were perfused with K-H solution containing 200 μmol/L methyl-β-cyclodextrin at 40 min before ischemia, and the other treatments were similar to those previously described in group IR.At the end of 15 min of equilibration (T 0) and 5 and 10 min of reperfusion (T 1, 2), coronary outflow was collected for determination of actate dehydrogenase (LDH) activity by chemical colorimetry.Myocardial infarct size (IS) and area at risk (AAR) were measured, and IS/AAR was calculated at the end of 120 min reperfusion.Myocardial tissues of left ventricle were taken to detect the expression of Cav-3, ERK1/2 and phosphorylated ERK1/2 (p-ERK1/2) by Western blot, and p-ERK1/2/ERK1/2 ratio was calculated. Results:Compared with group IR, IS, IS/AAR and LDH activity in coronary outflow were significantly decreased, the expression of Cav-3 was up-regulated, and p-ERK1/2/ERK1/2 ratio was increased in group MP ( P<0.05). Compared with group MP, IS, IS/AAR and LDH activity in coronary outflow were significantly increased, the expression of Cav-3 was down-regulated, and p-ERK1/2/ERK1/2 ratio was decreased in group MP+ MβCD ( P<0.05). Conclusions:The mechanism by which morphine preconditioning reduces I/R injury may be related to activation of Cav-3/ERK signaling pathway in rats with chronic heart failure.
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Objective:Clamping bilateral renal arteries with refined surgical methods to establish the rat renal ischemia-reperfusion injury (RIRI) model, and study the protective mechanism of ischemic preconditioning renal (IPC) tubular cell-derived exosomes in RIRI.Methods:25 female Sprague Dawley (SD) rats were divided into sham group, model group, inactivated group, normoxic group, IPC group. In the sham operation group, after bilateral renal arteries were dissociated, the back incision was disinfected and closed. The model group established RIRI model; RIRI models were established in inactivated group, normoxia group and IPC group, and then 200 μg of inactivated exosomes, normal exosomes and IPC exosomes were injected into the caudal vein 24 hours after operation. Serum creatinine (Scr) and urea nitrogen (BUN) levels were detected. The pathological changes of renal tissue were observed under light microscope. Transmission electron microscopy (TEM) was used to observe the shape and size of renal tubular exosomes. Nanoparticle tracking analysis (NTA)was used to detect the concentration and size of renal tubular exosomes.Results:Compared with the sham group, the Scr and BUN levels in the model group were significantly elevated ( P<0.01). Renal pathological changes in the model group showed damaged of the tubular structure, necrosis and shedding of tubular epithelial cells, and a large number of inflammatory cells accumulated in the renal interstitial tissue with varying degrees of edema. Compared with the inactivated group, the Scr and BUN levels significantly decreased in the normoxic group and IPC group ( P<0.01). Renal pathological changes in the normoxic group and IPC group showed that the renal tubular cell necrosis alleviated, inflammatory was reduced, the improved edema. Compared with the normoxic group, the Scr and BUN levels in the IPC group were further reduced ( P<0.01). Renal pathological changes in the IPC group showed that the inflammatory cells were significantly reduced, the cell edema was significantly improved, and the cell apoptosis was significantly reduced. Conclusions:Clamping bilateral renal arteries with refined surgical methods is the main and optimal way to build a rat model of RIRI. IPC tubular cell-derived exosomes have protective and repair effects on RIRI.
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Objective:To explore the clinical application value of limb remote ischemic postconditioning (LRIPC) in patients with acute cerebral infarction after recanalization.Methods:A total of 78 patients with acute cerebral infarction admitted to the First Affiliated Hospital of Shantou University Medical College from June 2017 to March 2019 were selected. According to the random number table method, they were divided into the observation group with 39 cases (LRIPC + conventional medical treatment) and the control group with 39 cases (conventional medical treatment). The National Institutes of Health Stroke Scale (NIHSS) and Montreal Cognitive Assessment scale (MoCA) scores, the changes of cerebral blood perfusion, cerebral infarction volume and the levels of nerve function indexes before and after the treatment were compared and analyzed.Results:After the treatment, the NIHSS scores in the observation group were lower than thosein the control group, and the MoCA scores were higher than those in the control group, the differences were statistically significant ( P<0.05). After the treatment, the mean transit time of cerebral blood flow in the observation group was shorter than that in the control group, while the regional cerebral blood flow and regional cerebral blood volume were higher than those in the control group, the differences were statistically significant ( P<0.05). After the treatment, the volume of cerebral infarction in the observation group was lower than that in the control group ( P<0.05). After the treatment, the levels of matrix metalloproteinase 9 and S-100B protein in the observation group were lower than those in the control group: (142.45 ± 36.23) mg/L vs. (176.89 ± 42.63) mg/L, (2.52 ± 0.46) μg/L vs. (3.61 ± 0.75) μg/L; and the level of nerve growth factor was higher than that in the control group: (143.49 ± 10.58) μg/L vs. (124.96 ± 13.62) μg/L, the differences were statistically significant ( P<0.05). Conclusions:LRIPC can improve the nerve functions, cognitive functions andreduce the volume of cerebral infarction by improving cerebral blood flow. It also has a good effect on alleviating the neurological functional impairment after vascular recanalization.
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Objective:To investigate the efficacy of liposomal doxorubicin intensive preconditioning regimen and allogeneic hematopoietic stem cell transplantation (allo-HSCT) in treatment of leukemia.Methods:The data of 20 patients with intensive preconditioning regimen allo-HSCT who were admitted to Shenzhen Second People's Hospital from January 2016 to June 2017 were retrospectively analyzed. The transplantation effect, occurrence of complications and prognosis of patients were analyzed.Results:The median time of granulocyte engraftment was 17 d (13-23 d); the median time of platelet engraftment was 22.5 d (minimum 13 d, maximum >90 d). The acute graft-versus-host disease (GVHD) and chronic GVHD occurred in 2 cases and 1 case, respectively. Eight cases occurred hemorrhagic cystitis, 15 cases occurred Epstein-Barr viremia, 8 cases occurred cytomegaloviremia, 1 case occurred sepsis, 1 case occurred acute liver injury, and 2 cases occurred fungal pneumonia. The median follow-up time was 31.7 months (0.8-53.8 months). One patient died of intracranial infection on the 25th day after transplantation; 3 patients relapsed during the follow-up period, and 2 of them died; the other 16 patients carried 100% donor genes during the follow-up period.Conclusions:The liposomal doxorubicin intensive preconditioning regimen and allo-HSCT have a good effect on leukemia. Increasing the intensity of pretreatment does not increase the treatment-related adverse reactions. The incidence rates of Epstein-Barr viremia and cytomegaloviremia are high, but they are improved after active treatment.
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Objective:To investigate the effect of different ischemic preconditioning (IPC) modes on ischemia-reperfusion (IR) injury of skeletal muscle in rats.Methods:Forty male SD rats were selected to construct the model of IR injury of skeletal muscle by clamping one side of the femoral artery. In the IPC mode, the right femoral artery was clipped for 10 minutes, and reperfusion ensued for 10 minutes after the release of artery clamp. Such preconditioning procedure was repeated 3 times. The rats were divided into conventional IR group, IPC immediate group, IPC24-hour group, IPC48-hour group and sham operation group according to the random number table method, with 8 rats in each group.In conventional IR group, the right femoral artery was clipped for 3 hours and then the artery clamp was released to allow reperfusion for 3 hours. In IPC immediate group, the same treatment as conventional IR group was performed immediately after preconditioning. In IPC24-hour group, the rats received skin suturing after preconditioning and then fed in a cage for 24 hours before the same treatment as conventional IR group. In IPC48-hour group, the rats received skin suturing after preconditioning and then fed in a cage for 48 hours before the same treatment as conventional IR group. In sham operation group, the right femoral artery was bluntly separated but not clipped. At the end of reperfusion, the tibialis anterior muscle tissue, gastrocnemius muscle tissue and serum were collected. The ratio of wet weight to dry weight (W/D) of the tibialis anterior muscle tissue was calculated to evaluate tissue edema. After HE staining, histopathological changes of gastrocnemius muscle were observed and the injury severity of gastrocnemius tissue was scored. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and malondialdehyde (MDA) were determined by ELISA. Expressions of hypoxia receptor (EGLN1) and hypoxia-inducible factor-1α (HIF-1α) in the gastrocnemius tissue were detected by real-time fluorescence quantitative PCR (qRT-PCR).Results:The degree of tissue edema was reduced under different IPC modes when compared with conventional IR group (all P<0.01). The W/D in conventional IR group, IPC immediate group, IPC24-hour group and IPC48-hour group were 6.05±0.19, 5.70±0.12, 5.25±0.13 and 5.50±0.08, higher than 3.80±0.08 in sham operation group (all P<0.01). IPC24-hour group had the least degree of edema when compared with IPC immediate group and IPC48-hour group ( P<0.05 or 0.01). The muscle fibers in sham operation group were neatly arranged with clear structure, and the muscle fibers in other groups showed different degrees of injury and inflammatory infiltration. The total scores for tissue injury severity in IPC immediate group, IPC24-hour group and IPC48-hour group were (8.15±0.15)points, (6.15±0.38)points and (6.90±0.19)points, lower than (9.60±0.50)points in conventional IR group and higher than (0.16±0.16)points in sham operation group (all P<0.01). The total scores for tissue injury severity in IPC24-hour group and IPC48-hour group were not significantly different ( P>0.05), but both decreased when compared with IPC immediate group ( P<0.05 or 0.01). ELISA showed that the levels of TNF-α, IL-1β and MDA under different IPC modes were higher than those in sham operation group (all P<0.01), and the order from high to low was conventional IR group, IPC immediate group, IPC48-hour group, IPC24-hour group and sham operation group. Levels of IL-1β, TNF-α and MDA in IPC24-hour group were decreased when compared with IPC immediate group and IPC48-hour group (all P<0.05). qRT-PCR showed that the expression of EGLN1 mRNA from high to low was conventional IR group, IPC48-hour group, sham operation group, IPC immediate group and IPC24-hour group and that the expression of EGLN1 mRNA in IPC24-hour group decreased when compared with conventional IR group, IPC immediate group and IPC48-hour group (all P<0.01). The expression of HIF-1α mRNA increased under different IPC modes when compared with sham operation group (all P<0.01), and the order from high to low was IPC24-hour group, IPC immediate group, IPC48-hour group, conventional IR group and sham operation group. The expression of HIF-1α mRNA in IPC24-hour group increased when compared with conventional IR group, IPC immediate group and IPC48-hour group ( P<0.05 or 0.01), but there was no significant difference between IPC immediate group and IPC48-hour group ( P>0.05). Conclusions:Different ischemic preconditioning modes can reduce IR injury of skeletal muscle in rats by reducing tissue edema, inflammatory symptoms and oxidative stress response, among which reperfusion 24 hours after IPC has the best effect on IR injury. EGLN1 and HIF-1α may be involved in IPC to alleviate IR injury of skeletal muscle in rats.
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Objective:To investigate the protective effect of lipopolysaccharide (LPS) preconditioning on cerebral ischemia reperfusion in rats.Methods:One hundred and twenty adult male SD rats were randomly divided into sham operation group, model group, low-dose LPS group (0.05 mg/kg), medium-dose LPS group (0.15 mg/kg), and high-dose LPS group (0.45 mg/kg). LPS was injected intraperitoneally for preconditioning, once a day for 7 consecutive days. Twenty-four hours after the last injection, the left middle cerebral artery occlusion model was induced by suture-occluded method. The model was reperfused 1.5 h after ischemia. At 24 h after reperfusion, the neurological deficit was evaluated by neurobehavioral score. The volume of cerebral infarction was measured by triphenyltetrazolium chloride staining. The serum levels of proinflammatory cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α were detected by enzyme-linked immunosorbent assay. The expression of Toll-like receptor 4 (TLR4), matrix metalloproteinase (MMP) -2 and MMP-9 in ischemic brain tissue was detected by Western blot analysis.Results:Compared with the sham operation group, blood-brain barrier permeability was increased in the model group, serum IL-1β, IL-6 and TNF-α were up-regulated, and the expression of TLR4, MMP-2 and MMP-9 proteins in ischemic brain tissue was up-regulated. Compared with the model group, the neurological impairment of each LPS intervention group was significantly reduced, the volume of cerebral infarction was significantly reduced, the permeability of blood-brain barrier was significantly reduced, the serum IL-1β, IL-6 and TNF-α were down-regulated, and the expression of TLR4, MMP-2 and MMP-9 protein in ischemic brain tissue was down-regulated, especially in the medium-dose group and the high-dose group.Conclusions:LPS preconditioning can induce the formation of ischemic tolerance, inhibit the activation of TLR4-MMP-2/MMP-9 signal pathway, reduce the damage and inflammation of blood-brain barrier structure, and thus play a neuroprotective role in rats with cerebral ischemia reperfusion.
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Kidney transplantation is more efficacious compared with other organ transplantations. Nevertheless, postoperative complications, such as renal ischemia-reperfusion injury (IRI), severely affect the survival rate and quality of life of recipients. How to mitigate the IRI of renal allografts has become one of the key topics in the field of kidney transplantation. At present, ischemic preconditioning enables renal allografts to adapt to ischemia, which is one of the effective methods to prevent the progression of IRI. However, the underlying mechanism remains elusive. In this article, the application of ischemic preconditioning in IRI, the regulation mechanism of ischemic preconditioning on the IRI of renal allografts at the cellular level and intracellular signaling pathway, and clinical application value and prospect of ischemic preconditioning were reviewed, aiming to provide reference for alleviating the IRI of renal allografts, enhancing the survival rate of the recipients and renal allografts and improving the quality of life of recipients.
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Abstract Caveolin, the protein of the caveolar membrane, interacts and binds with endothelial nitric oxide synthase (eNOS), forming a caveolin-eNOS complex leading to suppression of the eNOS activity. Caveolin, therefore, maintains eNOS in the inactivated state leading to reduced nitric oxide (NO) production. Ischemic preconditioning disrupts the caveolin-eNOS complex leading to activation of the eNOS and thus results in cardioprotection. During ischemic preconditioning, NO produces cardioprotection by the opening of the KATP channel, and the caveolin forms a suitable signalling platform facilitating the interaction of NO with the KATP channel. Estrogen deficiency has been reported to upregulate caveolin-1 expression. The article aims to review the various mechanisms that placed the women at the risk of coronary artery diseases after postmenopausal estrogen deficiency and their role in the cardioprotective effect of ischemic preconditioning.
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Role , Women , Coronary Artery Disease/complications , Postmenopause/metabolism , Caveolins/analysis , Ischemic Preconditioning/adverse effects , Nitric OxideABSTRACT
Abstract This study investigated the protective effect of dexmedetomidine (Dex) on lung injury during one-lung ventilation (OLV) in elderly patients undergoing radical esophagectomy with remote ischemic preconditioning (RIPC). Fifty-four esophageal cancer patients undergoing radical esophagectomy were divided into control, RIPC and RIPC+Dex group. During the anesthesia and ventilation in surgery, the RIPC was performed in RIPC group, and the intravenous infusion of Dex based on RIPC was conducted in RIPC+Dex group. At the time immediately before OLV beginning (T1), 60 min of OLV (T2) and end of surgery (T3), the oxygenation index (OI) and respiratory index (RI) were recorded, and the serum superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) levels were determined. Results showed that, compared with RIPC group, in RIPC+Dex group the OI at T2 and T3 increased, the RI at T2 and T3 decreased, the serum SOD level at T3 increased, the serum MDA level at T3 decreased, the serum TNF-α and IL-6 levels at T2 and T3 decreased (all P < 0.05). In conclusion, for elderly patients undergoing radical esophagectomy with RIPC, Dex can effectively inhibit the oxidative stress and inflammatory response during OLV, thus alleviating the lung injury and reducing the postoperative complications.
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Abstract Ischemic heart disease is the leading cause of death in postmenopausal women. The activity of heart ACE increases whereas the activity of ACE-2 decreases after menopause. The present study was designed to investigate the role of ACE and ACE-2 in the abrogated cardioprotective effect of IPC in OVX rat heart. The heart was isolated from OVX rat and mounted on Langendorff's apparatus for giving intermittent cycles of IPC. The infarct size was estimated using TTC stain, and coronary effluent was analyzed for LDH, CK-MB, and nitrite release. IPC induced cardioprotection was significantly attenuated in the ovariectomized rat heart as compared to the normal rat heart. However, this attenuated cardioprotection was significantly restored by perfusion of DIZE, an ACE-2 activator, and captopril, an ACE inhibitor, alone or in combination noted in terms of decrease in myocardial infarct size, the release of LDH and CK-MB, and also increase in the release of NO as compared to untreated OVX rat heart. Thus, it is suggested that DIZE and captopril, alone or in combination restore the attenuated cardioprotective effect of IPC in OVX rat heart which is due to an increase in ACE-2 activity and decrease in ACE activity after treatment.