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OBJECTIVE: This study evaluated the efficacy and safety of limb ischemic preconditioning (LIPC) in treating restless leg syndrome (RLS) in maintenance hemodialysis (MHD) patients. METHODS: A total number of 45 patients participated in the study. They were randomly divided into LIPC group and control group. The LIPC was performed by inflating the limb ischemic preconditioning training device in the patient's thigh to 200 mmHg to create transient ischemia, whereas control group inflated the device to 20 mmHg. International Restless Legs Syndrome (IRLS), Clinical Global Impression Scale (CGI-S), and Medical Outputs Study Sleep Scale were employed to evaluate LIPC effectiveness. The primary endpoint was the 'rate of clinical improvement in RLS severity', defined as the percentage of patients who had an IRLS score decrease of ≥5 points in each group. RESULTS: After intervention, the rate of clinical improvement in RLS severity was 56.5% in the LIPC group and 13.6% in the control group (13 (56.5) vs 3 (13.6), p = 0.003). In addition, the LIPC group's IRLS, CGI-S scores, the sleep disturbance and somnolence scores showed a significant downward trend compared to the control group (-5.5 ± 5.3 vs - 1.0 ± 3.8, p = 0.002; -1.7 ± 1.2 vs - 0.5 ± 1.4, p = 0.003; -15.5 ± 17.8 vs 3.7 ± 12.0, p < 0.001; -9.9 ± 18.8 vs - 2.4 ± 8.6, p = 0.003). During the study, there were no serious adverse event in any of the patients. CONCLUSIONS: LIPC could be employed to effectively and safely alleviate the RLS symptoms in MHD patients.

Asunto(s)

Precondicionamiento Isquémico , Síndrome de las Piernas Inquietas , Trastornos del Sueño-Vigilia , Humanos , Síndrome de las Piernas Inquietas/complicaciones , Síndrome de las Piernas Inquietas/terapia , Síndrome de las Piernas Inquietas/diagnóstico , Método Doble Ciego , Diálisis Renal , Resultado del Tratamiento , Índice de Severidad de la Enfermedad

RESUMEN

INTRODUCTION: The aim of this study was to investigate the efficacy and safety of limb ischemia preconditioning (LIPC) in the treatment of intradialytic hypotension (IDH) in patients with maintenance hemodialysis (MHD). METHODS: This was a single-center, prospective, and randomized controlled case study. A total of 38 patients with MHD who met the inclusion criteria from September 2021 to August 2022 were selected from the Blood Purification Center of our hospital. They were randomly divided into the LIPC group (n = 19) and the control group (n = 19). For patients in the LIPC group, the femoral artery blood flow was blocked with an LIPC instrument for 5 min (pressurized to 200 mm Hg) before each dialysis, and they were reperfused for 5 min. The cycle was repeated five times, with a total of 50 min for 12 weeks. The control group was pressurized to 20 mm Hg with an LIPC instrument, and the rest was the same as the LIPC group. The blood pressure of 0 h, 1 h, 2 h, 3 h, 4 h, and body weight before and after hemodialysis were measured in the two groups during hemodialysis, the incidence of IDH and the changes of serum troponin I (TNI) and creatine kinase isoenzyme MB (CK-MB) levels before and after the intervention were observed, and the ultrafiltration volume and ultrafiltration rate were recorded. RESULTS: At the 8th and 12th week after intervention, the MAP in the LIPC group was higher than that in the control group (103.28 ± 12.19 mm Hg vs. 93.18 ± 11.11 mm Hg, p = 0.04; 101.81 ± 11.36 mm Hg vs. 91.81 ± 11.92 mm Hg, p = 0.047). The incidence of IDH in the LIPC group was lower than that in the control group (36.5% vs. 43.1%, p = 0.01). The incidence of clinical treatment in IDH patients in the LIPC group was lower than that in the control group (6.3% vs. 12.4%, p = 0.00). The incidence of early termination of hemodialysis in the LIPC group was lower than that in the control group (1.6% vs. 3.8%, p = 0.01). The levels of TNI and CK-MB in the LIPC group after the intervention were lower than those in the control group (322.30 ± 13.72 ng/dL vs. 438.50 ± 24.72 ng/dL, p = 0.00; 159.78 ± 8.48 U/dL vs. 207.00 ± 8.70 U/dL, p = 0.00). The changes of MAP before and after the intervention were negatively correlated with the changes of TNI and CK-MB before and after the intervention (r = -0.473, p = 0.04; r = -0.469, p = 0.04). There were no differences in dry body mass and ultrafiltration rate between the two groups before and after the LIPC intervention (p > 0.05). Multiple linear regression analysis shows that TNI is the main influencing factor of ΔMAP. No LIPC-related adverse events were found during the study period. CONCLUSION: LIPC can effectively reduce the incidence of IDH in patients with MHD and may be associated with the alleviation of myocardial damage.

Asunto(s)

Hipotensión , Precondicionamiento Isquémico , Fallo Renal Crónico , Humanos , Diálisis Renal/efectos adversos , Estudios Prospectivos , Hipotensión/etiología , Hipotensión/prevención & control , Presión Sanguínea , Fallo Renal Crónico/terapia

RESUMEN

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.

RESUMEN

The mechanism for limb ischemic precondition (RLIPC)-induced suppression of reperfusion arrhythmia remains unknown. The purpose of this study was to examine the roles of the pro-survival reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways in this RLIPC-mediated antiarrhythmic activity. Male Sprague Dawley rats were assigned to sham-operated, control, or RLIPC groups. All rats except for the sham rats had 5 min of left main coronary artery occlusion with another 20 min of reperfusion. RLIPC was initiated by four cycles of limb ischemia (5 min) and reperfusion (5 min) on the bilateral femoral arteries. Hearts in every group were taken for protein phosphorylation analysis. RLIPC ameliorated reperfusion-induced arrhythmogenesis and reduced the incidence of sudden cardiac death during the entire 20-min reperfusion period (66.7% of control rats had SCD vs. only 16.7% of RLIPC-treated rats). RLIPC enhances ventricular ERK1/2 phosphorylation after reperfusion. RLIPC-induced antiarrhythmic action and ERK1/2 phosphorylation are abolished in the presence of the ERK1/2 inhibitor U0126. Limb ischemic preconditioning protects the heart against myocardial reperfusion injury-induced lethal arrhythmia. These beneficial effects may involve the activation of ERK1/2 in the RISK signaling pathway.

Asunto(s)

Precondicionamiento Isquémico Miocárdico , Daño por Reperfusión Miocárdica , Animales , Antiarrítmicos/farmacología , Antiarrítmicos/uso terapéutico , Arritmias Cardíacas/etiología , Arritmias Cardíacas/prevención & control , Humanos , Isquemia , Masculino , Daño por Reperfusión Miocárdica/metabolismo , Ratas , Ratas Sprague-Dawley , Reperfusión , Sobrevivientes

RESUMEN

PURPOSE: Contrast-induced acute kidney injury (CI-AKI) resulting from administration of iodinated contrast media (CM) is the third leading cause of hospital-acquired acute kidney injury and is associated with substantial morbidity and mortality. Deteriorated renal microcirculation plays an important role in CI-AKI. Limb ischemic preconditioning (LIPC), where brief and non-injurious ischemia/reperfusion is applied to a limb prior to the administration of the contrast agent, is emerging as a promising strategy for CI-AKI prevention. However, it is not known whether the renal protection of LIPC against CI-AKI is mediated by regulation of renal microcirculation and the molecular mechanisms remain largely unknown. METHODS: In this study, we examined the renal cortical and medullary blood flow in a stable CI-AKI model using 5/6-nephrectomized (NE) rat. The LIPC and sham procedures were performed prior to the injection of CM. Furthermore, we analyzed renal medulla hypoxia using in vivo labeling of hypoxyprobe. Pharmacological inhibitions and western blotting were used to determine the underlying molecular mechanisms. RESULTS: In this study, we found LIPC significantly ameliorated CM-induced reduction of medullary blood flow and attenuated CM-induced hypoxia. PI3K inhibitor (wortmannin) treatment blocked the regulation of medullary blood flow and the attenuation of hypoxia of LIPC. Phosphorylation of Akt/eNOS was significantly decreased via wortmannin treatment compared with LIPC. Nitric oxide synthase-inhibitor [Nω-nitro-L-arginine methyl ester (L-NAME)] treatment abolished the above effects and decreased phosphorylation of eNOS, but not Akt. CONCLUSIONS: Collectively, the results demonstrate that LIPC ameliorates CM-induced renal vasocontraction and is mediated by activation of PI3K/Akt/eNOS signaling pathway.

Asunto(s)

Lesión Renal Aguda/metabolismo , Extremidades/irrigación sanguínea , Riñón/metabolismo , Microcirculación/fisiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Apoptosis/efectos de los fármacos , Extremidades/fisiopatología , Precondicionamiento Isquémico/métodos , Riñón/fisiopatología , Fosfatidilinositol 3-Quinasas/metabolismo , Ratas Sprague-Dawley , Daño por Reperfusión/metabolismo , Transducción de Señal/fisiología

RESUMEN

Our previous studies have demonstrated that limb ischemic preconditioning (LIP) induced brain ischemic tolerance and up-regulated the expression of p38 MAPK and ERK in the hippocampal CA1 region in rats. The present study was undertaken to investigate the role of adenosine in brain protection and up-regulation of p38 MAPK and ERK induced by LIP. It was found that adenosine A1 receptor antagonist DPCPX dose-dependently inhibited the protective effect of LIP. The up-regulation of p38 MAPK and ERK induced by LIP could be blocked by DPCPX. Furthermore, we observed the effect of adenosine on the brain ischemia. The results showed that pre-administration of adenosine could partly mimic the neuroprotective effect on the brain, up-regulate the expression of p38 MAPK and ERK. Based on the above results, it can be concluded that adenosine participated in brain protection and up-regulation of the expression of p38 MAPK and ERK during the induction of brain ischemic tolerance after LIP.

Asunto(s)

Adenosina/metabolismo , Isquemia Encefálica/metabolismo , Extremidades/irrigación sanguínea , Precondicionamiento Isquémico/métodos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Isquemia Encefálica/terapia , Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/metabolismo , Sistema de Señalización de MAP Quinasas , Masculino , Antagonistas de Receptores Purinérgicos P1/farmacología , Ratas , Ratas Wistar , Receptor de Adenosina A1/metabolismo , Activación Transcripcional , Regulación hacia Arriba/efectos de los fármacos , Xantinas/farmacología

RESUMEN

BACKGROUND/AIMS: Protein kinase C(PKC)-ε activation is a mechanism of preconditioning cardioprotection but its role in repeated non-invasive limb ischemic preconditioning (rNLIP) mediated cardioprotection against myocardial ischemia/reperfusion (I/R) injury in diabetes is unknown. METHODS: Eight-week streptozotocin-induced diabetic and non-diabetic Sprague-Dawley rats were subjected to I/R without or with rNLIP. In vitro, H9C2 cells were cultured with high glucose (HG) and subjected to hypoxia/re-oxygenation (H/R) without or with PKC-ε or STAT3 gene knock-down in the absence or presence of remote time hypoxia preconditioning (HPC). RESULTS: Diabetic rats displayed larger post-ischemic myocardial infarct size and higher troponin-I release with concomitant cardiac PKC-ԑ overexpression and activation manifested as increased membrane translocation, while phosphorylated STAT3 (p-STAT3) and Akt (p-Akt) were lower compared to non-diabetic rats (all P<0.05). rNLIP reduced infarct size in both non-diabetic and diabetic rats. rNLIP reduced post-ischemic cardiac PKC-ԑ activation in diabetic while increased PKC-ԑ activation in non-diabetic rats, resulting in increased cardiac p-STAT3 and p-Akt. In H9C2 cells, HG increased PKC-ԑ expression and exacerbated post-H/R injury, accompanied with reduced p-STAT3 and p-Akt, which were all reverted by HPC. These HPC protective effects were abolished by either PKC-ԑ or STAT3 gene knock-down, except that PKC-ԑ gene knock-down reverted HG and H/R-induced reduction of p-STAT3. CONCLUSION: rNLIP attenuates diabetic heart I/R injury by mitigating HG-induced PKC-ԑ overexpression and, subsequently, activating STAT3.

Asunto(s)

Diabetes Mellitus Experimental/patología , Daño por Reperfusión Miocárdica/prevención & control , Proteína Quinasa C-epsilon/metabolismo , Factor de Transcripción STAT3/metabolismo , Animales , Hipoxia de la Célula , Línea Celular , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Glucosa/farmacología , Precondicionamiento Isquémico , L-Lactato Deshidrogenasa/metabolismo , Masculino , Potencial de la Membrana Mitocondrial , Daño por Reperfusión Miocárdica/patología , Oxígeno/farmacología , Fosforilación , Proteína Quinasa C-epsilon/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Ratas , Ratas Sprague-Dawley , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/genética , Transducción de Señal , Estreptozocina/toxicidad , Troponina I/metabolismo , Proteína X Asociada a bcl-2/metabolismo

RESUMEN

Remote limb ischemic preconditioning (RIPC) is a clinically feasible strategy to protect against ischemia/reperfusion injury, but the knowledge concerning the mechanism underlying RIPC is scarce. This study was performed to examine the effect of RIPC on brain tissue suffering from ischemia challenge and explore its underlying mechanism in a rat model. The animals were divided into four groups: Sham, middle cerebral artery occlusion (MCAO), RIPC, and MCAO+RIPC. We found that previous exposure to RIPC significantly attenuated neurological dysfunction and lessened brain edema in MCAO+RIPC group. Moreover, other important events were observed in MCAO+RIPC group, including substantial decrements in the concentrations of oxidative response indicators [malondialdehyde (MDA), 8-hydroxy-2-deoxyguanosine (8-OHdG), and protein carbonyl], significant reductions in levels of inflammation mediators [myeloperoxidase (MPO), tumor necrosis factor-a (TNF-a), interleukin-1ß (IL-1ß), and IL-6], and significant decline in neuronal apoptosis revealed by a smaller number of TUNEL-positive cells. Interestingly, both MCAO and RIPC groups exhibited meaningful elevations in the levels of HIF-1a, HSP70, and AMP-activated protein kinase (AMPK) compared to Sham group, and previous exposure to RIPC further elevated the levels of HIF-1a, HSP70, and AMPK in MCAO+RIPC group. Furthermore, the administration of YC-1 (HIF-1 inhibitor), 8-bAMP (AMPK inhibitor), and Quercetin (HSP70 inhibitor) to MCAO+RIPC rats demonstrated that HIF-1α/AMPK/HSP70 was involved in RIPC-mediated protection against cerebral ischemia.

Asunto(s)

Proteínas Quinasas Activadas por AMP/metabolismo , Isquemia Encefálica/prevención & control , Extremidades/irrigación sanguínea , Proteínas HSP70 de Choque Térmico/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Precondicionamiento Isquémico , Neuroprotección , Transducción de Señal , Animales , Apoptosis , Edema Encefálico/complicaciones , Edema Encefálico/patología , Isquemia Encefálica/complicaciones , Isquemia Encefálica/patología , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/patología , Inflamación/complicaciones , Inflamación/patología , Masculino , Neuronas/patología , Estrés Oxidativo , Ratas Sprague-Dawley

RESUMEN

AIM:To study the effects of noninvasive delayed limb ischemia preconditioning ( NDLIP) on ani-mal cardiac function , myocardial morphology and myocardial apoptosis after myocardial infarction ( MI ) .METHODS:Healthy SD male rats [n=45, weighing (250 ±10) g] were randomly divided into 3 groups:MI group:the animal model of MI was established by surgical ligation of left anterior descending artery ( LAD) after 2 weeks;NDLIP group:after the success of the MI animal model , NDLIP was carried out every other day until the 4th, 6th and 8th weeks;sham group:as the negative control group , the animals were taken heart LAD threading but no ligation .All rats were fed conventionally .At the end of the 4th, 6th and 8th weeks, all rats were made ventricular intubation , and then the hemodynamic parameters were recorded .The blood samples were withdrawn from the abdominal aorta and the serum was separated via centrifugation . The serum contents of Bcl-2 and Bax were measured by ELISA .Left ventricular anterior wall was homogenized .The mito-chondrial respiratory chain complexes Ⅰ,Ⅱ,Ⅲand Ⅳin the myocardial tissues were detected by ELISA .RESULTS:At the end of the 4th, 6th and 8th weeks, compared with MI group, left ventricular systolic pressure in NDLIP group was significantly increased , while left ventricular end-diastolic pressure in NDLIP group was significantly decreased ( both P<0.05).Mitochondrial respiratory chain complexesⅠ, Ⅱ, Ⅲ and Ⅳ in NDLIP group were significantly increased (P<0.05).The serum level of Bcl-2 in NDLIP group was significantly increased and Bax level was reduced remarkably (both P<0.01) .CONCLUSION:NDLIP improves the hemodynamic indexes , promotes the mitochondrial respiratory function and inhibits cell apoptosis , thus improving the prognosis of MI .

RESUMEN

Clinical trials shows that remote ischemic preconditioning (IPC) can protect against contrast induced nephropathy (CIN) in risky patients, however, the exact mechanism is unclear. In this study, we explored whether renalase, an amine oxidase that has been previously shown to mediate reno-protection by local IPC, would also mediate the same effect elicited by remote IPC in animal model. Limb IPC was performed for 24h followed by induction of CIN. Our results indicated that limb IPC prevented renal function decline, attenuated tubular damage and reduced oxidative stress and inflammation in the kidney. All those beneficial effects were abolished by silencing of renalase with siRNA. This suggests that similar to local IPC, renalase is also critically involved in limb IPC-elicited reno-protection. Mechanistic studies showed that limb IPC increased TNFα levels in the muscle and blood, and up-regulated renalase and phosphorylated IκBα expression in the kidney. Pretreatment with TNFα antagonist or NF-κB inhibitor, largely blocked renalase expression. Besides, TNFα preconditioning increased expression of renal renalase in vivo and in vitro, and attenuated H2O2 induced apoptosis in renal tubular cells. Collectively, our results suggest that limb IPC-induced reno-protection in CIN is dependent on increased renalase expression via activation of the TNFα/NF-κB pathway.

Asunto(s)

Nefropatías Diabéticas/etiología , Precondicionamiento Isquémico , Riñón/irrigación sanguínea , Monoaminooxidasa/metabolismo , Animales , Caspasa 3/metabolismo , Línea Celular , Nefropatías Diabéticas/metabolismo , Modelos Animales de Enfermedad , Humanos , Peróxido de Hidrógeno/toxicidad , Riñón/patología , Masculino , Monoaminooxidasa/química , Monoaminooxidasa/genética , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Interferencia de ARN , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Regulación hacia Arriba/efectos de los fármacos

RESUMEN

Aim To study the preventative effects of noninvasive delayed limb ischemic preconditioning ( NDLIP) on sudden cardiac death in rats with myocar-dial infarction. Methods Thirty healthy SD male rats weighting ( 250 ± 10 ) g were randomly divided into 3 groups:① myocardial infarction ( MI ) group: animal model of MI was established by making surgical ligation of animal LAD. ② MI plus NDLIP group: after the success of the animal model of MI, NDLIP was carried out every other day until 4th week. ③Sham group:as the negative control group, animals were taken heart LAD threading but no ligation. All rats were fed con-ventionally. At the end of 4 weeks, three groups of rats were administered with metaraminol ( 0. 2 mg · min-1 ) . ECG, drug cumulant of sudden death and death onset time were recorded. After sudden death, blood samples were withdrawn from abdominal aorta and serum was separated via centrifugation. ELISA method was used to measure serum caspase-3 , HSP70 and SOD concentration. Results While metaraminol led animal cardiac sudden death, the rats heart rate ( HR) kept declining with the increase of dosage of metaraminol during the administration period. Rat HR of MI+NDLIP group [ ( 479 ± 8 ) vs ( 416 ± 19 ) beat ·min-1 , ( 446 ± 32 ) vs ( 370 ± 20 ) beat · min-1 , (376 ± 53) vs (305 ± 29) beat·min-1, (307 ± 63) vs (244 ± 33) beat·min-1, (283 ± 45) vs (121 ± 35 ) beat · min-1 , P <0. 01 ] was markedly higher than that of MI group at 0 , 5 , 10 , 30 , 50 min before death. Compared with MI group, drugs cumulant to sudden death and death onset time of MI + NDLIP group [ ( 14. 58 ± 3. 03 ) vs ( 10. 76 ± 2. 73 ) mg, (72. 9 ± 15. 2 ) vs ( 53. 8 ± 13. 6 ) min, P <0. 01 ] were significantly increased. Compared with MI group, serum caspase-3 content of MI+NDLIP group was sig-nificantly reduced [ ( 2. 01 ± 0. 52 ) vs ( 2. 34 ± 0. 38 )μg·L-1 , P<0. 01 ]; HSP70 levels were remarkably increased [ ( 3. 01 ± 0. 58 ) vs ( 2. 70 ± 0. 43 ) μg · L-1 , P <0. 05 ]; SOD levels were significantly im-proved [(1. 99 ± 0. 65) vs (1. 70 ± 0. 58) mg·L-1, P<0. 01 ] . Conclusion NDLIP can prevent sudden cardiac death after myocardial infarction in rats, which may be mediated by reducing the myocardial cell apop-tosis, increasing protective protein expression and en-hancing antioxidant capacity.

RESUMEN

Contrast-induced acute kidney injury (CI-AKI) resulting from the use of intravascular iodinated contrast media for diagnostic and interventional cardiovascular procedures is associated with substantial morbidity and mortality. Despite preventative measures intended to mitigate the risk of CI-AKI, there remains a need for a novel and effective therapeutic approach. Limb ischemic preconditioning (LIPC), where short-term ischemia/reperfusion is applied to an arm prior to administration of the contrast agent, has been shown in several trials to preserve renal function in patients at high risk for CI-AKI. However, the underlying mechanism by which this procedure provides renoprotection against contrast media insults is not known. Here, we explored the molecular mechanism(s) of LIPC-induced protection of the kidneys from CI-AKI, particularly the role of phosphorylated glycogen synthase kinase-3ß (GSK-3ß). We used a novel CI-AKI model consisting of 5/6 nephrectomized (NE) rats at 6 weeks after the ablative surgery. LIPC- or sham-treated rats were administered iohexol (10 ml/kg, 3.5 gI) via the tail vein. The results showed that LIPC protected the kidneys against iohexol-induced injury. This protective effect was accompanied by the attenuation of renal dysfunction, tubular damage, apoptosis, mitochondrial swelling, oxidative stress, and inflammation. Furthermore, LIPC-induced renoprotection was blocked via treatment with inhibitors of PI3K (wortmannin or LY294002), but not ERK (U0126 or PD98059). LIPC also increased the protein expression levels of phospho-Akt, phospho-GSK-3ß, and nuclear Nrf2, and decreased the levels of nuclear NF-κB. A specific GSK-3ß inhibitor (SB216763) mimicked this effect of LIPC, by inhibiting the opening of the mitochondrial permeability transition pore and reducing the levels of oxidative stress and inflammation via activation of Nrf2 and suppression of NF-κB. The above results demonstrate that LIPC induces protection against CI-AKI, making this procedure a promising strategy for preventing CI-AKI. In particular, this renoprotective effect involves the phosphorylation of GSK-3ß.

Asunto(s)

Lesión Renal Aguda/terapia , Medios de Contraste/efectos adversos , Glucógeno Sintasa Quinasa 3/metabolismo , Yohexol/efectos adversos , Precondicionamiento Isquémico , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/genética , Lesión Renal Aguda/patología , Androstadienos/farmacología , Animales , Apoptosis/efectos de los fármacos , Cromonas/farmacología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Glucógeno Sintasa Quinasa 3/genética , Glucógeno Sintasa Quinasa 3 beta , Indoles/farmacología , Túbulos Renales/efectos de los fármacos , Túbulos Renales/metabolismo , Túbulos Renales/patología , Masculino , Maleimidas/farmacología , Proteínas de Transporte de Membrana Mitocondrial/antagonistas & inhibidores , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Morfolinas/farmacología , Factor 2 Relacionado con NF-E2/agonistas , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/antagonistas & inhibidores , FN-kappa B/genética , FN-kappa B/metabolismo , Nefrectomía , Estrés Oxidativo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/agonistas , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Wortmanina

RESUMEN

@#Objective To observe the brain glucose metabolism after limb ischemic preconditioning (LIPC) for ischemic moyamoya disease with positron emission tomography (PET) and statistical parametric mapping (SPM). Methods 62 patients with ischemic moyamoya disease were enrolled and randomized into LIPC group (n=31) and control group (n=31). The glucose metabolism of patients was analyzed with PET before and after treatment in both groups, using the methods of radioactivity ratio and SPM. Results The glucose metabolism ratio improved more in the LIPC group than in the control group (P<0.01), and aggravated less than in the control group (P<0.001). As setting the glucose metabolism increased after treatment, there were 7 areas activated in LIPC group, including frontal, temporal and parietal lobes, and the KE=1121; while there were 5 areas activated in the control group, including frontal and parietal lobes, and the KE=292. As setting the glucose metabolism decreased after treatment, there was only frontal area activated in LIPC group, while there were 8 areas activated in the control group, including frontal, parietal, occipital lobes, and the KE=629. Conclusion LIPC may improve the brain glucose metabolism in patients with moyamoya disease, which can be observed with PET and SPM.

RESUMEN

Objective To observe the brain glucose metabolism after limb ischemic preconditioning (LIPC) for ischemic moyamoya dis-ease with positron emission tomography (PET) and statistical parametric mapping (SPM). Methods 62 patients with ischemic moyamoya disease were enrolled and randomized into LIPC group (n=31) and control group (n=31). The glucose metabolism of patients was analyzed with PET before and after treatment in both groups, using the methods of radioactivity ratio and SPM. Results The glucose metabolism ratio improved more in the LIPC group than in the control group (P<0.01), and aggravated less than in the control group (P<0.001). As setting the glucose metabolism increased after treatment, there were 7 areas activated in LIPC group, including frontal, temporal and parietal lobes, and the KE=1121;while there were 5 areas activated in the control group, including frontal and parietal lobes, and the KE=292. As setting the glu-cose metabolism decreased after treatment, there was only frontal area activated in LIPC group, while there were 8 areas activated in the con-trol group, including frontal, parietal, occipital lobes, and the KE=629. Conclusion LIPC may improve the brain glucose metabolism in pa-tients with moyamoya disease, which can be observed with PET and SPM.

RESUMEN

AIM: To investigate the effects of the sera from the rats after limb ischemic preconditioning (LIPC) on human umbilical vein endothelial cells (HUVECs) injured by hydrogen peroxide (H2O2).METHODS:The HUVECs were divided into 5 groups:the cells in control group were cultured without any intervention;the cells in model group (M) were damaged by 1 mmol/L H2O2 for 2 h;the cells in early preconditioning serum (EPS) group, delayed pre-conditioning serum (DPS) group or sham limb ischemic preconditioning serum (SPS) group were treated with the corre-sponding serum at 5%for 12 h, respectively , and then treaed with H 2 O2 for 2 h.The viability of the HUVECs was ana-lyzed by flow cytometry .The lactate dehydrogenase ( LDH) in the culture media was detected .The cell adhesion molecules in the HUVECs were detected by real-time PCR.The mRNA and protein expression of heme oxygenase-1 (HO-1) was also determined .RESULTS:The viability of HUVECs incubated with 1 mmol/L H2 O2 for 2 h significantly decreased compared with the control cells , which was accompanied with the augmentations of LDH in the medium and the cell adhesion mole -cules in cells , such as vascular cell adhesion molecule-1 ( VCAM-1 ) and intercellular adhesion molecule-1 ( ICAM-1 ) . Preincubation with EPS and DPS derived from the rats subjected LIPC attenuated these injuries .Furthermore, pretreatment with EPS and DPS increased the expression of HO-1 at mRNA and protein levels .CONCLUSION:LIPC protects the HU-VECs from H2O2-induced injury.

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Ischemic brain injury is not uncommon after open-heart surgery with cardiopulmonary bypass and seriously undermines the patients' life quality. Therefore, potential protective effects of limb ischemic preconditioning (LIP) on subsequent ischemic injury of the brain were investigated by evaluating anti-inflammatory effects and apoptosis of pyramidal neurons in the CA1 hippocampus. One hundred and eight Sprague-Dawley rats were divided into the middle cerebral artery occlusion (MCAO) group (n=54) and the LIP group (n=54). A thread was used to occlude the middle cerebral artery in the MCAO group and the LIP group animals were pretreated with LIP followed by MCAO. In the two groups, nine samples were collected at each time-point of 0, 6, 12, 24, 48 and 72 h after MCAO to detect IL-6 and IL-17 and their mRNA levels. Neurological severity scores (NSS) were examined before the animals were sacrificed. Compared with the LIP group, cerebral histopathological changes in the MCAO group were most distinct and significantly more infiltrated inflammatory and apoptotic neuronal cells were observed at 24, 48 and 72 h post-surgery. IL-17 and IL-6 mRNA levels analyzed by quantitative real-time polymerase chain reaction (PCR) (qRT-PCR) were significantly reduced in the LIP group compared with the MCAO group at the 12, 24 and 48 h time-points. A significant reduction in IL-17 expression level was determined by enzyme-linked immunosorbent assay (ELISA) in the LIP group at 12, 24 and 48 h, while IL-6 was significantly reduced at the 24 and 48 h time-points. The NSSs were not significantly different between the groups. Therefore, in a MCAO rat model, we have proved that LIP pretreatment can protect the brain from infarction after ischemic injury and induce ischemic tolerance, potentially, by reducing IL-17 to provide anti-inflammatory effects and attenuate apoptosis of hippocampal neuronal cells.

Asunto(s)

Apoptosis , Isquemia Encefálica/sangre , Isquemia Encefálica/terapia , Miembro Posterior/irrigación sanguínea , Hipocampo/metabolismo , Precondicionamiento Isquémico , Células Piramidales/metabolismo , Animales , Modelos Animales de Enfermedad , Hipocampo/patología , Interleucina-17/sangre , Interleucina-6/sangre , Masculino , Células Piramidales/patología , Ratas , Ratas Sprague-Dawley , Factores de Tiempo

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Aims To investigate the protective effects of noninvasive limb ischemic preconditioning (LIPC) on myocardial ischemia-reperfusion (I /R)injury,and to explore the mechanism.Methods Healthy male Wistar rats were divided randomly into I /R,I /R +LIPC,I /R +5-Hydroxydecanoate (5-HD)and I /R +LIPC +5-HD groups.The I /R +LIPC and I /R +LIPC-5-HD groups of rats were subjected to three cy-cles of LIPC induction per day with 5 min of reperfu-sion after occlusion for 5 min at the left hind limb for 3 days.All rats were subjected to myocardial I /R injury on the fourth day.The I /R +5-HD and I /R +LIPC-5-HD groups of rats were given the inhibitor of ATP-sen-sitive potassium channel 5-HD before and during myo-cardial I /R injury. Results Compared with I /R group,LIPC reduced myocardial infarct size (P <0.05),lowered cardiocyte apoptosis index and Fas, FasL positive cell number (P <0.01 ),increased the reduced nitric oxide (NO)/endothelin (ET)-1 ratio (P <0.05)in serum in I /R +LIPC group.5-HD a-bolished the protective effects induced by LIPC in I /R+LIPC-5-HD group.Compared with normal myocardi-al tissue,expression of mir-30a-3p was increased in I /R group (P <0.01 )and was decreased in LIPC group (P <0.01 ).Conclusion LIPC alleviates myocardial I /R injury and improves endothelial function. The mechanism may be related with the opening of ATP-sensitive potassium channel,regulating the balance be-tween NO and ET-1 and decreasing the expression of myocardial mir-30a-3p.

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The aim of this study was to investigate the effect of limb ischemic preconditioning (LIPC) on myocardial apoptosis in myocardial ischemia-reperfusion injury (MIRI), as well as the regulation of caspase-3 and the B cell lymphoma 2 (Bcl-2) gene in LIPC. A total of 50 rats were divided randomly into 5 groups (n=10). Four rats in each group were drawn out for detection of apoptosis. The sham, MIRI and LIPC groups underwent surgery without additional treatment. In the LY294002 group, LY294002 preconditioning was administered 15 min before reperfusion. In the LY294002+LIPC group, following LIPC, LY294002 was administered 15 min before reperfusion. The relative expression of myocardial Bcl-2 and caspase-3 mRNA and the apoptotic index for each group were determined by reverse transcription-polymerase chain reaction (RT-PCR) and terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL), respectively. The ultrastructure of the cardiac muscle tissues was observed by election microscopy. Compared with the sham group, the expression of caspase-3 mRNA in the MIRI group significantly increased (P<0.05) and the expression of Bcl-2 mRNA clearly decreased. Compared with the MIRI group, LIPC reduced the expression of caspase-3 and increased the expression of Bcl-2 mRNA (P<0.05). There were no significant differences between the LY294002+LIPC group and the MIRI group. Compared with the sham group, the apoptotic index of myocardial cells in the MIRI group significantly increased (P<0.05). Compared with the MIRI group, LIPC significantly decreased the apoptotic index of myocardial cells (P<0.05) and LY294002 increased the apoptotic index of myocardial cells. Compared with the LIPC group, LY294002+LIPC significantly increased the apoptotic index of myocardial cells (P<0.05). There were no significant differences between the LY294002+LIPC and MIRI groups. In conclusion, LIPC increased the expression of Bcl-2 and decreased caspase-3 mRNA and apoptosis in myocardial tissue following MIRI. Therefore, LIPC plays a protective role in myocardial tissue.