Background:Remote ischemic perconditioning(RIPerC)has been demonstrated to protect grafts from hepatic ischemia-reperfusion injury(IRI).This study investigated the role of exosomes in RIPerC of liver grafts in rats.Me...Background:Remote ischemic perconditioning(RIPerC)has been demonstrated to protect grafts from hepatic ischemia-reperfusion injury(IRI).This study investigated the role of exosomes in RIPerC of liver grafts in rats.Methods:Twenty-five rats(including 10 donors)were randomly divided into five groups(n=5 each group):five rats were used as sham-operated controls(Sham),ten rats were for orthotopic liver transplantation(OLT,5 donors and 5 recipients)and ten rats were for OLT+RIPerC(5 donors and 5 recipients).Liver architecture and function were evaluated.Results:Compared to the OLT group,the OLT+RIPerC group exhibited significantly improved liver graft histopathology and liver function(P<0.05).Furthermore,the number of exosomes and the level of P-Akt were increased in the OLT+RIPerC group.Conclusions:RIPerC effectively improves graft architecture and function,and this protective effect may be related to the increased number of exosomes.The upregulation of P-Akt may be involved in underlying mechanisms.展开更多
In remote ischemic conditioning(RIC), several cycles of ischemia and reperfusion render distant organ and tissues more resistant to the ischemia-reperfusion injury. The intermittent ischemia can be applied before the ...In remote ischemic conditioning(RIC), several cycles of ischemia and reperfusion render distant organ and tissues more resistant to the ischemia-reperfusion injury. The intermittent ischemia can be applied before the ischemic insult in the target site(remote ischemic preconditioning), during the ischemic insult(remote ischemic perconditioning) or at the onset of reperfusion(remote ischemic postconditioning). The mechanisms of RIC have not been completely defined yet; however, these mechanisms must be represented by the release of humoral mediators and/or the activation of a neural reflex. RIC has been discovered in the heart, and has been arising great enthusiasm in the cardiovascular field. Its efficacy has been evaluated in many clinical trials, which provided controversial results. Our incomplete comprehension of the mechanisms underlying the RIC could be impairing the design of clinical trials and the interpretation of their results. In the present review we summarize current knowledge about RIC pathophysiology and the data about its cardioprotective efficacy.展开更多
Acute coronary syndromes remain a leading single cause of death worldwide. Therapeutic strategies to treat cardiomyocyte threatening ischemia/reperfusion injury are urgently needed. Remote ischemic preconditioning(r I...Acute coronary syndromes remain a leading single cause of death worldwide. Therapeutic strategies to treat cardiomyocyte threatening ischemia/reperfusion injury are urgently needed. Remote ischemic preconditioning(r IPC) applied by brief ischemic episodes to heartdistant organs has been tested in several clinical studies, and the major body of evidence points to beneficial effects of r IPC for patients. The underlying signaling, however, remains incompletely understood. This relates particularly to the mechanism by which the protective signal is transferred from the remote site to the target organ. Many pathways have been forwarded but none can explain the protective effects completely. In light of recent experimental studies, we here outline the current knowledge relating to the generation of the protective signal in the remote organ, the signal transfer to the target organ and the transduction of the transferred signal into cardioprotection. The majority of studies favors a humoral factor that activates cardiomyocyte downstream signaling- receptor-dependent and independently. Cellular targets include deleterious calcium(Ca2+) signaling, reactive oxygen species, mitochondrial function and structure, and cellular apoptosis and necrosis. Following an outline of the existing evidence, we will furthermore characterize the existing knowledge and discuss future perspectives with particular emphasis on the interaction between the recently discovered hypoxic nitrite-nitric oxide signaling in r IPC. This refers to the protective role of nitrite, which can be activated endogenously using r IPC and which then contributes to cardioprotection by rIPC.展开更多
Intestinal ischemia is a severe disorder with a variety of causes.Reperfusion is a common occurrence during treatment of acute intestinal ischemia but the injury resulting from ischemia/reperfusion(IR)may lead toeven ...Intestinal ischemia is a severe disorder with a variety of causes.Reperfusion is a common occurrence during treatment of acute intestinal ischemia but the injury resulting from ischemia/reperfusion(IR)may lead toeven more serious complications from intestinal atrophy to multiple organ failure and death.The susceptibility of the intestine to IR-induced injury(IRI)appears from various experimental studies and clinical settings such as cardiac and major vascular surgery and organ transplantation.Where as oxygen free radicals,activation of leukocytes,failure of microvascular perfusion,cellular acidosis and disturbance of intracellular homeo-stasis have been implicated as important factors inthe pathogenesis of intestinal IRI,the mechanisms underlying this disorder are not well known.To date,increasing attention is being paid in animal studies to potential pre-and post-ischemia treatments that protect against intestinal IRI such as drug interference with IR-induced apoptosis and inflammation processes and ischemic pre-conditioning.However,better insight is needed into the molecular and cellular events associated with reperfusion-induced damage to develop effective clinical protection protocols to combat this disorder.In this respect,the use of ischemic post-conditioning in combination with experimentally prolonged acidosis blocking deleterious reperfusion actions may turn out to have particular clinical relevance.展开更多
AIM:To investigate the protective effects of remote ischemic postconditioning(RIP)against limb ischemiareperfusion(IR)-induced gastric mucosal injury.METHODS:Gastric IR was established in male Wistar rats by placing a...AIM:To investigate the protective effects of remote ischemic postconditioning(RIP)against limb ischemiareperfusion(IR)-induced gastric mucosal injury.METHODS:Gastric IR was established in male Wistar rats by placing an elastic rubber band under a pressure of 290-310 mmHg on the proximal part of both lower limbs for 3 h followed by reperfusion for 0,1,3,6,12or 24 h.RIP was performed using three cycles of 30 s of reperfusion and 30 s of reocclusion of the femoral aortic immediately after IR and before reperfusion for up to 24 h.Rats were randomly assigned to receive IR(n=36),IR followed by RIP(n=36),or sham treatment(n=36).Gastric tissue samples were collected from six animals in each group at each timepoint and processed to determine levels of malondialdehyde(MDA),superoxide dismutase(SOD),xanthine oxidase(XOD)and myeloperoxidase(MPO).Additional samples were processed for histologic analysis by hematoxylin and eosin staining.Blood samples were similarly collected to determine serum levels of lactate dehydrogenase(LDH),creatine kinase(CK),tumor necrosis factor(TNF)-αand interleukin(IL)-10.RESULTS:The pathologic changes in gastric tissue induced by IR were observed by light microscopy.Administration of RIP dramatically reduced the gastric damage score after 6 h of reperfusion(5.85±0.22 vs7.72±0.43;P<0.01).In addition,RIP treatment decreased the serum activities of LDH(3.31±0.32 vs 6.46±0.03;P<0.01),CK(1.94±0.20 vs 4.54±0.19;P<0.01)and the concentration of TNF-α(53.82±0.85vs 88.50±3.08;P<0.01),and elevated the concentration of IL-10(101.46±5.08 vs 99.77±4.32;P<0.01)induced by IR at 6 h.Furthermore,RIP treatment prevented the marked elevation in MDA(3.79±0.29vs 6.39±0.81)content,XOD(7.81±0.75 vs 10.37±2.47)and MPO(0.47±0.05 vs 0.82±0.03)activities,and decrease in SOD(4.95±0.32 vs 3.41±0.38;P<0.01)activity in the gastric tissue as measured at 6 h.CONCLUSION:RIP provides effective functional protection and prevents cell injury to gastric tissue induced by limb IR via anti-inflammatory and antioxidant actions.展开更多
BACKGROUND Studies suggested that remote ischemic preconditioning(RIPC)may effectively lessen the harmful effects of ischemia reperfusion injury during organ transplantation surgery.AIM To investigate the protective e...BACKGROUND Studies suggested that remote ischemic preconditioning(RIPC)may effectively lessen the harmful effects of ischemia reperfusion injury during organ transplantation surgery.AIM To investigate the protective effects of RIPC on living liver donors and recipients following pediatric liver transplantation.METHODS From January 2016 to January 2019 at Renji Hospital Affiliated with Shanghai Jiao Tong University School of Medicine,208 donors were recruited and randomly assigned to four groups:S-RIPC group(no intervention;n=55),D-RIPC group(donors received RIPC;n=51),R-RIPC group(recipients received RIPC,n=51)and DR-RIPC group(both donors and recipients received RIPC;n=51).We primarily evaluated postoperative liver function among donors and recipients and incidences of early allograft dysfunction,primary nonfunction and postoperative complications among recipients.RESULTS RIPC did not significantly improve alanine transaminase and aspartate aminotransferase levels among donors and recipients or decrease the incidences of early allograft dysfunction,primary nonfunction,and postoperative complications among recipients.Limited protective effects were observed,including a lower creatinine level in the D-RIPC group than in the S-RIPC group on postoperative day 0(P<0.05).However,no significant improvements were found in donors who received RIPC.Furthermore,RIPC had no effects on the overall survival of recipients.CONCLUSION The protective effects of RIPC were limited for recipients who received living liver transplantation,and no significant improvement of the prognosis was observed in recipients.展开更多
Three cycles of remote ischemic pre-conditioning induced by temporarily occluding the bilateral femoral arteries (10 minutes) prior to 10 minutes of reperfusion were given once a day for 3 days before the animal recei...Three cycles of remote ischemic pre-conditioning induced by temporarily occluding the bilateral femoral arteries (10 minutes) prior to 10 minutes of reperfusion were given once a day for 3 days before the animal received middle artery occlusion and reperfusion surgery. The results showed that brain infarct volume was significantly reduced after remote ischemic pre-conditioning. Scores in the forelimb placing test and the postural reflex test were significantly lower in rats having undergone remote ischemic pre-conditioning compared with those who did not receive remote ischemic pre-conditioning. Thus, neurological function was better in rats having undergone remote ischemic pre-conditioning compared with those who did not receive remote ischemic pre-conditioning. These results indicate that remote ischemic pre-conditioning in rat hindlimb exerts protective effects in ischemia-reperfusion injury.展开更多
AIM To investigate the underlying mechanisms of the protective role of remote ischemic perconditioning(RIPerC) in rat liver transplantation. METHODS Sprague-Dawley rats were subjected to sham, orthotopic liver transpl...AIM To investigate the underlying mechanisms of the protective role of remote ischemic perconditioning(RIPerC) in rat liver transplantation. METHODS Sprague-Dawley rats were subjected to sham, orthotopic liver transplantation(OLT), ischemic postconditioning(IPostC) or RIPerC. After 3 h reperfusion, blood samples were taken for measurement of alanine aminotransferase, aspartate aminotransferase, creatinine(Cr) and creatinine kinase-myocardial band(CK-MB). The liver lobes were harvested for the following measurements: reactive oxygen species(ROS), H2O2, mitochondrial membrane potential(ΔΨm) and total nitric oxide(NO). These measurements were determined using an ROS/H2O2, JC1 and Total NOx Assay Kit, respectively. Endothelial NO synthase(e NOS) was analyzed by reverse transcription-polymerase chain reaction(RTPCR) and western blotting, and peroxynitrite was semiquantified by western blotting of 3-nitrotyrosine. RESULTS Compared with the OLT group, the grafts subjected to RIPerC showed significantly improved liver and remote organ functions(P < 0.05). ROS(P < 0.001) including H2O2(P < 0.05) were largely elevated in the OLT group as compared with the sham group, and RIPerC(P < 0.05) reversed this trend. The collapse of ΔΨm induced by OLT ischemia/reperfusion(I/R) injury was significantly attenuated in the RIPerC group(P < 0.001). A marked increase of NO content and phosphoserine eN OS, both in protein and mR NA levels, was observed in liver graft of the RIPer C group as compared with the OLT group(P < 0.05). I/R-induced 3-nitrotyrosine content was significantly reduced in the RIPerC group as compared with the OLT group(P < 0.05). There were no significant differences between the RIPerC and IPostC groups for all the results except Cr. The Cr level was lower in the RIPerC group than in the IPostC group(P < 0.01).CONCLUSION Liver graft protection by RIPerC is similar to or better than that of IPostC, and involves inhibition of oxidative stress and up-regulation of the PI3K/Akt/e NOS/NO pathway.展开更多
Common gastrointestinal diseases such as radiation enteritis(RE),acute pancreatitis,inflammatory bowel diseases(IBD)and drug-induced hepatotoxicity share pathophysiological mechanisms at the molecular level,mostly inv...Common gastrointestinal diseases such as radiation enteritis(RE),acute pancreatitis,inflammatory bowel diseases(IBD)and drug-induced hepatotoxicity share pathophysiological mechanisms at the molecular level,mostly involving the activation of many pathways of the immune response,ultimately leading to tissue injury.Increased oxidative stress,inflammatory cytokine release,inflammatory cell infiltration and activation and the up-regulation of inflammatory transcription factors participate in the pathophysiology of these complex entities.Treatment varies in each specific disease,but at least in the cases of RE and IBD immunosuppressors are effective.However,full therapeutic responses are not always achieved.The pathophysiology of ischemiareperfusion(IR)injury shares many of these mechanisms.Brief and repetitive periods of ischemia in an organ or limb have been shown to protect against subsequent major IR injury in distant organs,a phenomenon called remote ischemic preconditioning(RIP).This procedure has been shown to protect the gut,pancreas and liver by modulating many of the same inflammatory mechanisms.Since RIP is safe and tolerable,and has shown to be effective in some recent clinical trials,I suggest that RIP could be used as a physiologicallyrelevant adjunct treatment for non-ischemic gastrointestinal inflammatory conditions.展开更多
It is difficult to control the degree of ischemic postconditioning in the brain and other ischemia-sensitive organs.Remote ischemic postconditioning could protect some ischemia-sensitive organs through measures on ter...It is difficult to control the degree of ischemic postconditioning in the brain and other ischemia-sensitive organs.Remote ischemic postconditioning could protect some ischemia-sensitive organs through measures on terminal organs.In this study,a focal cerebral ischemia-reperfusion injury model was established using three cycles of remote ischemic postconditioning,each cycle consisted of 10-minute occlusion of the femoral artery and 10-minute opening.The results showed that,remote ischemic postconditioning significantly decreased the percentage of the infarct area and attenuated brain edema.In addition,inflammatory nuclear factor-κB expression was significantly lower,while anti-apoptotic Bcl-2 expression was significantly elevated in the cerebral cortex on the ischemic side.Our findings indicate that remote ischemic postconditioning attenuates focal cerebral ischemia/reperfusion injury,and that the neuroprotective mechanism is mediated by an anti-apoptotic effect and reduction of the inflammatory response.展开更多
AIM To investigate the protective mechanism of mitofusin-2(Mfn2) in rat remote ischemic perconditioning(RIC) models and revalidate it in alpha mouse liver-12(AML-12) hypoxia cell lines.METHODS Sprague-Dawley rats were...AIM To investigate the protective mechanism of mitofusin-2(Mfn2) in rat remote ischemic perconditioning(RIC) models and revalidate it in alpha mouse liver-12(AML-12) hypoxia cell lines.METHODS Sprague-Dawley rats were divided into three groups(n = 6 each): sham, orthotopic liver transplantation and RIC. After operation, blood samples were collected to test alanine aminotransferase and aspartate aminotransferase. The liver lobes were harvested for histopathological examination, western blotting(WB) and quantitative real-time(q RT)-PCR. AML-12 cell lines were then subjected to normal culture, anoxic incubator tank culture(hypoxia) and anoxic incubator tank culture with Mfn2 knockdown(hypoxia + Si), and data of q RT-PCR, WB, mitochondrial membrane potential(ΔΨm), apoptosis, endoplasmic reticulum Ca2+ concentrations and mitochondrial Ca2+ concentrations were collected.RESULTS Both sham and normal culture groups showed no injury during the experiment. The RIC group showed amelioration of liver function compared with the orthotopic liver transplantation group(P < 0.05). q RTPCR and WB confirmed that Mfn2-mitochondrial Ca2+ uptake 1/2(MICUs) axis was changed(P < 0.005). In AML-12 cell lines, compared with the hypoxia group, the hypoxia + Si group attenuated the collapse of ΔΨm and apoptosis(P < 0.005). The endoplasmic reticulum Ca2+ decrease and mitochondrial Ca2+ overloading observed in the hypoxia group were also attenuated in the hypoxia + Si group(P < 0.005). Finally, q RT-PCR and WB confirmed the Mfn2-MICUs axis change in all the groups(P < 0.005).CONCLUSION Mfn2 participates in liver injury in rat RIC models and AML-12 hypoxia cell lines by regulating the MICUs pathway.展开更多
AIM: To investigate the influence of remote ischemic preconditioning (RIPC) on anastomotic integrity. METHODS: Sixty male Wistar rats were randomized to six groups. The control group (n = 10) had an end-to-end ileal a...AIM: To investigate the influence of remote ischemic preconditioning (RIPC) on anastomotic integrity. METHODS: Sixty male Wistar rats were randomized to six groups. The control group (n = 10) had an end-to-end ileal anastomosis without RIPC. The preconditioned groups (n = 34) varied in time of ischemia and time of reperfusion. One group received the amino acid L-arginine before constructing the anastomosis (n = 9). On postoperative day 4, the rats were re-laparotomized, and bursting pressure, hydroxyproline concentration, intra-abdominal adhesions, and a histological score concerning the mucosal ischemic injury were collected. The data are given as median (range).RESULTS: On postoperative day 4, median bursting pressure was 124 mmHg (60-146 mmHg) in the control group. The experimental groups did not show a statistically significant difference (P > 0.05). Regarding the hydroxyproline concentration, we did not find any significant variation in the experimental groups. We detected significantly less mucosal injury in the RIPC groups. Furthermore, we assessed more extensive intra-abdominal adhesions in the preconditioned groups than in the control group. CONCLUSION: RIPC directly before performing small bowel anastomosis does not affect anastomotic stability in the early period, as seen in ischemic preconditioning.展开更多
AIM To study whether remote ischemic preconditioning(RIPC) has an impact on clinical outcomes, such as post-operative atrial fibrillation(POAF).METHODS This was a prospective, single-center, single-blinded,randomized ...AIM To study whether remote ischemic preconditioning(RIPC) has an impact on clinical outcomes, such as post-operative atrial fibrillation(POAF).METHODS This was a prospective, single-center, single-blinded,randomized controlled study. One hundred and two patients were randomized to receive RIPC(3 cycles of 5 min ischemia and 5 min reperfusion in the upper arm after induction of anesthesia) or no RIPC(control). Primary outcome was POAF lasting for five minutes or longer during the first seven days after surgery. Secondary outcomes included length of hospital stay, incidence of inpatient mortality, myocardial infarction, and stroke. RESULTS POAF occurred at a rate of 54% in the RIPC group and 41.2% in the control group(P = 0.23). No statistically significant differences were noted in secondary outcomes between the two groups. CONCLUSION This is the first study in the United States to suggest that RIPC does not reduce POAF in patients with elective or urgent cardiac surgery. There were no differences in adverse effects in either group. Further studies are required to assess the relationship between RIPC and POAF.展开更多
Integrity of the blood-brain barrier structure is essential for maintaining the internal environment of the brain.Development of cerebral infarction and brain edema is strongly associated with blood-brain barrier leak...Integrity of the blood-brain barrier structure is essential for maintaining the internal environment of the brain.Development of cerebral infarction and brain edema is strongly associated with blood-brain barrier leakage.Therefore,studies have suggested that protecting the blood-brain barrier may be an effective method for treating acute stroke.To examine this possibility,stroke model rats were established by middle cerebral artery occlusion and reperfusion.Remote ischemic postconditioning was immediately induced by three cycles of 10-minute ischemia/10-minute reperfusion of bilateral hind limbs at the beginning of middle cerebral artery occlusion reperfusion.Neurological function of rat models was evaluated using Zea Longa's method.Permeability of the blood-brain barrier was assessed by Evans blue leakage.Infarct volume and brain edema were evaluated using 2,3,5-triphenyltetrazolium chloride staining.Expression of matrix metalloproteinase-9 and claudin-5 m RNA was determined by real-time quantitative reverse transcription-polymerase chain reaction.Expression of matrix metalloproteinase-9 and claudin-5 protein was measured by western blot assay.The number of matrix metalloproteinase-9-and claudin-5-positive cells was analyzed using immunohistochemistry.Our results showed that remote ischemic postconditioning alleviated disruption of the blood-brain barrier,reduced infarct volume and edema,decreased expression of matrix metalloproteinase-9 m RNA and protein and the number of positive cells,increased expression of claudin-5 m RNA and protein and the number of positive cells,and remarkably improved neurological function.These findings confirm that by suppressing expression of matrix metalloproteinase-9 and claudin-5 induced by acute ischemia/reperfusion,remote ischemic postconditioning reduces blood-brain barrier injury,mitigates ischemic injury,and exerts protective effects on the brain.展开更多
BACKGROUND:Ischemic preconditioning(IPC) is a strategy to reduce ischemia-reperfusion(I/R) injury.The protective effect of remote ischemic preconditioning(RIPC) on liver I/R injury is not clear.This study aimed to inv...BACKGROUND:Ischemic preconditioning(IPC) is a strategy to reduce ischemia-reperfusion(I/R) injury.The protective effect of remote ischemic preconditioning(RIPC) on liver I/R injury is not clear.This study aimed to investigate the roles of RIPC in liver I/R in fatty liver rats and the involvement of endothelial nitric oxide synthase-nitric oxide(eNOS-NO) pathway and microRNA expressions in this process.METHODS:A total of 32 fatty rats were randomly divided into the sham group,I/R group,RIPC group and RIPC+I/R group.Serum alanine aminotransferase(ALT),aspartate aminotransferase(AST) and nitric oxide(NO) were measured.Hematoxylin-eosin staining was used to observe histological changes of liver tissues,TUNEL to detect hepatocyte apoptosis,and immunohistochemistry assay to detect heat shock protein 70(HSP70) expression.Western blotting was used to detect liver inducibleNOS(iNOS) and eNOS protein levels and realtime quantitative polymerase chain reaction to detect miR-34a,miR-122 and miR-27b expressions.RESULTS:Compared with the sham and RIPC groups,serum ALT,AST and iNOS in liver tissue were significantly higher in other two groups,while serum NO and eNOS in liver tissue were lower,and varying degrees of edema,degeneration and inflammatory cell infiltration were found.Cell apoptosis number was slightly lower in the RIPC+I/R group than that in I/R group.Compared with the sham group,HSP70 expressions were significantly increased in other three groups(all P<0.05).Compared with the sham and RIPC groups,elevated miR-34a expressions were found in I/R and RIPC+I/R groups(P<0.05).MiR-122 and miR-27b were found significantly decreased in I/R and RIPC+I/R groups compared with the sham and RIPC groups(all P<0.05).CONCLUSION:RIPC can reduce fatty liver I/R injury by affecting the eNOS-NO pathway and liver microRNA expressions.展开更多
Despite obvious progress in the treatment of acute forms of ischemic stroke, the risk of this condition remains unacceptably high. Brain infarction in the middle cerebral artery basin occurs in patients with atheroscl...Despite obvious progress in the treatment of acute forms of ischemic stroke, the risk of this condition remains unacceptably high. Brain infarction in the middle cerebral artery basin occurs in patients with atherosclerosis. The onset of the brain infarction is facilitated by the cessation of circulation (embolism) in conditions of insufficient collateral circulation. The extent of the infarct zone is determined by neuronal death and impaired microcirculation. The development of new methods for effective targeted restorative stroke therapy is crucial for restorative treatment and reducing the risk of mortality after stroke. Remote ischemic conditioning (RIC) is an approach to limiting reperfusion injury in the ischemic region of the brain after focal ischemia. One of the most commonly used <i>in vivo</i> models in stroke studies is the filament model of Middle Cerebral Artery Occlusion (MCAO) in rats. In our experiment, it was performed for 30 min (J. Koizumi) with subsequent 48-hour reperfusion. Within the first 24 hours after the start of reperfusion several short episodes of ischemia in low limbs were induced. After 48 hours of reperfusion the brains were harvested and stained with TTC. Then we evaluated the effect of RIC within 24 hours <i>ex vivo</i> in rats’ brains, as well as syndecan-1 plasma concentration. Infarct area was assessed by means of Image-Pro program with statistical analysis. Infarct volumes in the model group (31.97% ± 2.5%) were significantly higher compared to the values in the RIC group 48 hours after ischemia-reperfusion (13.6% ± 1.3%) (*P < 0.05). A significant reduction in the area of infarction after RIC is likely due to the effect on the regulation of collateral blood flow in the ischemia area. On the second day after ischemia-reperfusion, tissue swelling was reduced in the RIC group compared to the model group. Analysis of the average concentration of Syndecan-1 revealed the difference between model and RIC groups. Syndecan-1, endothelial glycocalyx protein, might be the regulator which performs vascular control of the interaction with inflammatory cell and is responsible for mediate effect of remote ischemic conditioning on the restriction of ischemic-reperfusion injury.展开更多
Ischemic stroke is a major neurological disease with limited effective therapeutic options except for thrombolysis and thrombectomy. Remote ischemic conditioning (RIC) is an approach that promises an alternative to th...Ischemic stroke is a major neurological disease with limited effective therapeutic options except for thrombolysis and thrombectomy. Remote ischemic conditioning (RIC) is an approach that promises an alternative to the current treatment portfolio. As an easy-handled, non-invasive regimen, it takes advantage of transient ischemia (currently often made through inflation and deflation of limb blood pressure cuff) to enhance the tolerance of vital organs to ischemia. RIC can be executed before, during and after the onset of stroke. The mechanisms of action of RIC employed at different stroke stages are similar and may involve humoral, neurological and inflammatory pathways. As new mechanisms underlying RIC-induced neuroprotection continue to be revealed, we review in this article some of the latest development in this field, including:① RIC and RIC-induced fundamental change, hypoxia, as well as the role of hypoxia inducible factors against stroke;② Potential role of RIC-induced extracellular vesicles in neuroprotection;③ RIC-induced metabolic changes in tissue protection;④ Potential effect of RIC on red blood cells (RBC) oxygen delivery;and ⑤ RIC and its anti-inflammatory potential.展开更多
Acute myocardial infarction initiates a cascade of events including loss of protein homeostasis and chronic inflammation that affect overall cellular repair and senescence. This contributes to loss of cardiomyocytes a...Acute myocardial infarction initiates a cascade of events including loss of protein homeostasis and chronic inflammation that affect overall cellular repair and senescence. This contributes to loss of cardiomyocytes and consequent formation of fibrotic scar. In certain vertebrate species, the heart can completely self-repair or regenerate after myocardial injury;however, this does not appear to be the case for humans. Despite this limitation, studies using novel non-pharmacologic interventions designed to protect against ischemic damage and to improve patient outcomes are ongoing. Remote ischemic conditioning stratagems are used to attenuate ischemia-reperfusion injury in clinical and animal studies;endogenous protective factors that stimulate complex signal transduction pathways are deemed responsible. Some of these factors could conceivably act in concert with those involved in regulating cardiovascular regeneration. Numerous studies have focused on cardiac regenerative interventions using stem-cell based therapies and transplantation of cardiomyocyte (or other cell types) or biocompatible matrices. This review discusses recent progress of pre-clinical and clinical translational studies for cardiac regeneration. In addition, we submit that interventions using cellular adjunctive therapies combined with remote ischemic conditioning may prove to be of interest in the battle to find novel strategies for protection against cardiac injury.展开更多
Background: Long-term remote ischemic conditioning (RIC) has been proven to be beneficial in multiple diseases, such as cerebral and cardiovascular diseases. However, the hyperacute and acute effects of a single RIC s...Background: Long-term remote ischemic conditioning (RIC) has been proven to be beneficial in multiple diseases, such as cerebral and cardiovascular diseases. However, the hyperacute and acute effects of a single RIC stimulus are still not clear. Quantitative proteomic analyses of plasma proteins following RIC application have been conducted in preclinical and clinical studies but exhibit high heterogeneity in results due to wide variations in experimental setups and sampling procedures. Hence, this study aimed to explore the immediate effects of RIC on plasma proteome in healthy young adults to exclude confounding factors of disease entity, such as medications and gender. Methods: Young healthy male participants were enrolled after a systematic physical examination and 6-month lifestyle observation. Individual RIC sessions included five cycles of alternative ischemia and reperfusion, each lasting for 5 min in bilateral forearms. Blood samples were collected at baseline, 5 min after RIC, and 2 h after RIC, and then samples were processed for proteomic analysis using liquid chromatography-tandem mass spectrometry method. Results: Proteins related to lipid metabolism (e.g., Apolipoprotein F), coagulation factors (hepatocyte growth factor activator preproprotein), members of complement cascades (mannan-binding lectin serine protease 1 isoform 2 precursor), and inflammatory responses (carboxypeptidase N catalytic chain precursor) were differentially altered at their serum levels following the RIC intervention. The most enriched pathways were protein glycosylation and complement/coagulation cascades. Conclusions: One-time RIC stimulus may induce instant cellular responses like anti-inflammation, coagulation, and fibrinolysis balancing, and lipid metabolism regulation which are protective in different perspectives. Protective effects of single RIC in hyperacute and acute phases may be exploited in clinical emergency settings due to apparently beneficial alterations in plasma proteome profile. Furthermore, the beneficial effects of long-term (repeated) RIC interventions in preventing chronic cardiovascular diseases among general populations can also be expected based on our study findings.展开更多
Ac ute myocardial infarction(AMI) is the leading cause of death and disability worldwide. Timely reperfusion is the standard of care and results in decreased infarct size, improving patient survival and prognosis. How...Ac ute myocardial infarction(AMI) is the leading cause of death and disability worldwide. Timely reperfusion is the standard of care and results in decreased infarct size, improving patient survival and prognosis. However, 25% of patients proceed to develop heart failure(HF) after myocardial infarction(MI) and 50% of these will die within fi ve years. Since the size of the infarct is the major predictor of the outcome, including the development of HF, therapies to improve myocardial salvage have great potential. Over the past three decades, a number of stimuli have been discovered that activate endogenous cardioprotective pathways. In ischemic preconditioning(IPC) and ischemic postconditioning, ischemia within the heart initiates the protection. Brief reversible episodes of ischemia in vascular beds remote from the heart can also trigger cardioprotection when applied before, during, or immediately after myocardial ischemia—known as remote ischemic pre-, per-, and post-conditioning, respectively. Although the mechanism of remote ischemic preconditioning(RIPC) has not yet been fully elucidated, many mechanistic components are shared with IPC. The discovery of RIPC led to research into the use of remote non-ischemic stimuli including nerve stimulation(spinal and vagal), and electroacupuncture(EA). We discovered and, with others, have elucidated mechanistic aspects of a nonischemic phenomenon we termed remote preconditioning of trauma(RPCT). RPCT operates via neural stimulation of skin sensory nerves and has similarities and differences to nerve stimulation and EA conducted at acupoints. We show herein that RPCT can be mimicked using electrical stimulation of the abdominal midline(EA-like treatment) and that this modality of activating cardioprotection is powerful as both a preconditioning and a postconditioning stimulus(when applied at reperfusion). Investigations of these cardioprotective phenomena have led to a more integrative understanding of mechanisms related to cardioprotection, and in the last five to ten years, it has become clear that the mechanisms aresimilar, whether induced by ischemic or non-ischemic stimuli. Taking together much of the data in the literature, we propose that all of these cardioprotective "conditioning" phenomena represent activation from different entry points of a cardiac conditioning network that converges upon specifi c mediators and effectors of myocardial cell survival, including NF-κB, Stat3/5, protein kinase C, bradykinin, and the mi to K ATP channel. Nervous system pathways may represent a novel mechanism for initiating conditioning of the heart and other organs. IPC and RIPC have proven difficult to translate clinically, as they have associated risks and cannot be used in some patients. Because of this, the use of neural and nociceptive stimuli is emerging as a potential non-ischemic and non-traumatic means to initiate cardiac conditioning. Clinical relevance is underscored by the demonstration of postconditioning with one of these modalities, supporting the conclusion that the development of pharmaceuticals and electroceuticals for this purpose is an area ripe for clinical development.展开更多
基金This study was supported by the Public Projects of Zhe-jiang Province(LGF21H030006)the Major Science and Tech-nology Projects of Hainan province(ZDKJ2019009)+2 种基金Research Project of Jinan Microecological Biomedicine Shandong Laboratory(JNL-2022002A,JNL-2022023C)Research Unit Project of Chinese Academy of Medical Sciences(2019-I2M-5-030)Innovative Re-search Groups of National Natural Science Foundation of China(81721091).
文摘Background:Remote ischemic perconditioning(RIPerC)has been demonstrated to protect grafts from hepatic ischemia-reperfusion injury(IRI).This study investigated the role of exosomes in RIPerC of liver grafts in rats.Methods:Twenty-five rats(including 10 donors)were randomly divided into five groups(n=5 each group):five rats were used as sham-operated controls(Sham),ten rats were for orthotopic liver transplantation(OLT,5 donors and 5 recipients)and ten rats were for OLT+RIPerC(5 donors and 5 recipients).Liver architecture and function were evaluated.Results:Compared to the OLT group,the OLT+RIPerC group exhibited significantly improved liver graft histopathology and liver function(P<0.05).Furthermore,the number of exosomes and the level of P-Akt were increased in the OLT+RIPerC group.Conclusions:RIPerC effectively improves graft architecture and function,and this protective effect may be related to the increased number of exosomes.The upregulation of P-Akt may be involved in underlying mechanisms.
文摘In remote ischemic conditioning(RIC), several cycles of ischemia and reperfusion render distant organ and tissues more resistant to the ischemia-reperfusion injury. The intermittent ischemia can be applied before the ischemic insult in the target site(remote ischemic preconditioning), during the ischemic insult(remote ischemic perconditioning) or at the onset of reperfusion(remote ischemic postconditioning). The mechanisms of RIC have not been completely defined yet; however, these mechanisms must be represented by the release of humoral mediators and/or the activation of a neural reflex. RIC has been discovered in the heart, and has been arising great enthusiasm in the cardiovascular field. Its efficacy has been evaluated in many clinical trials, which provided controversial results. Our incomplete comprehension of the mechanisms underlying the RIC could be impairing the design of clinical trials and the interpretation of their results. In the present review we summarize current knowledge about RIC pathophysiology and the data about its cardioprotective efficacy.
文摘Acute coronary syndromes remain a leading single cause of death worldwide. Therapeutic strategies to treat cardiomyocyte threatening ischemia/reperfusion injury are urgently needed. Remote ischemic preconditioning(r IPC) applied by brief ischemic episodes to heartdistant organs has been tested in several clinical studies, and the major body of evidence points to beneficial effects of r IPC for patients. The underlying signaling, however, remains incompletely understood. This relates particularly to the mechanism by which the protective signal is transferred from the remote site to the target organ. Many pathways have been forwarded but none can explain the protective effects completely. In light of recent experimental studies, we here outline the current knowledge relating to the generation of the protective signal in the remote organ, the signal transfer to the target organ and the transduction of the transferred signal into cardioprotection. The majority of studies favors a humoral factor that activates cardiomyocyte downstream signaling- receptor-dependent and independently. Cellular targets include deleterious calcium(Ca2+) signaling, reactive oxygen species, mitochondrial function and structure, and cellular apoptosis and necrosis. Following an outline of the existing evidence, we will furthermore characterize the existing knowledge and discuss future perspectives with particular emphasis on the interaction between the recently discovered hypoxic nitrite-nitric oxide signaling in r IPC. This refers to the protective role of nitrite, which can be activated endogenously using r IPC and which then contributes to cardioprotection by rIPC.
文摘Intestinal ischemia is a severe disorder with a variety of causes.Reperfusion is a common occurrence during treatment of acute intestinal ischemia but the injury resulting from ischemia/reperfusion(IR)may lead toeven more serious complications from intestinal atrophy to multiple organ failure and death.The susceptibility of the intestine to IR-induced injury(IRI)appears from various experimental studies and clinical settings such as cardiac and major vascular surgery and organ transplantation.Where as oxygen free radicals,activation of leukocytes,failure of microvascular perfusion,cellular acidosis and disturbance of intracellular homeo-stasis have been implicated as important factors inthe pathogenesis of intestinal IRI,the mechanisms underlying this disorder are not well known.To date,increasing attention is being paid in animal studies to potential pre-and post-ischemia treatments that protect against intestinal IRI such as drug interference with IR-induced apoptosis and inflammation processes and ischemic pre-conditioning.However,better insight is needed into the molecular and cellular events associated with reperfusion-induced damage to develop effective clinical protection protocols to combat this disorder.In this respect,the use of ischemic post-conditioning in combination with experimentally prolonged acidosis blocking deleterious reperfusion actions may turn out to have particular clinical relevance.
基金Supported by Lanzhou City Science and Technology Development Plan,No.2009-1-52
文摘AIM:To investigate the protective effects of remote ischemic postconditioning(RIP)against limb ischemiareperfusion(IR)-induced gastric mucosal injury.METHODS:Gastric IR was established in male Wistar rats by placing an elastic rubber band under a pressure of 290-310 mmHg on the proximal part of both lower limbs for 3 h followed by reperfusion for 0,1,3,6,12or 24 h.RIP was performed using three cycles of 30 s of reperfusion and 30 s of reocclusion of the femoral aortic immediately after IR and before reperfusion for up to 24 h.Rats were randomly assigned to receive IR(n=36),IR followed by RIP(n=36),or sham treatment(n=36).Gastric tissue samples were collected from six animals in each group at each timepoint and processed to determine levels of malondialdehyde(MDA),superoxide dismutase(SOD),xanthine oxidase(XOD)and myeloperoxidase(MPO).Additional samples were processed for histologic analysis by hematoxylin and eosin staining.Blood samples were similarly collected to determine serum levels of lactate dehydrogenase(LDH),creatine kinase(CK),tumor necrosis factor(TNF)-αand interleukin(IL)-10.RESULTS:The pathologic changes in gastric tissue induced by IR were observed by light microscopy.Administration of RIP dramatically reduced the gastric damage score after 6 h of reperfusion(5.85±0.22 vs7.72±0.43;P<0.01).In addition,RIP treatment decreased the serum activities of LDH(3.31±0.32 vs 6.46±0.03;P<0.01),CK(1.94±0.20 vs 4.54±0.19;P<0.01)and the concentration of TNF-α(53.82±0.85vs 88.50±3.08;P<0.01),and elevated the concentration of IL-10(101.46±5.08 vs 99.77±4.32;P<0.01)induced by IR at 6 h.Furthermore,RIP treatment prevented the marked elevation in MDA(3.79±0.29vs 6.39±0.81)content,XOD(7.81±0.75 vs 10.37±2.47)and MPO(0.47±0.05 vs 0.82±0.03)activities,and decrease in SOD(4.95±0.32 vs 3.41±0.38;P<0.01)activity in the gastric tissue as measured at 6 h.CONCLUSION:RIP provides effective functional protection and prevents cell injury to gastric tissue induced by limb IR via anti-inflammatory and antioxidant actions.
基金Supported by Renji Hospital Clinical Innovation Foundation,No.PYIII-17-002Outstanding Academic Leaders’Program of Health and Family Planning Commission of Shanghai,No.2017BR042+1 种基金Investigative Doctor Program(2017)of Shanghai Jiao Tong University School of MedicineJoint Project of Health and Family Planning Commission of Pudong District,No.PW2015D-3.
文摘BACKGROUND Studies suggested that remote ischemic preconditioning(RIPC)may effectively lessen the harmful effects of ischemia reperfusion injury during organ transplantation surgery.AIM To investigate the protective effects of RIPC on living liver donors and recipients following pediatric liver transplantation.METHODS From January 2016 to January 2019 at Renji Hospital Affiliated with Shanghai Jiao Tong University School of Medicine,208 donors were recruited and randomly assigned to four groups:S-RIPC group(no intervention;n=55),D-RIPC group(donors received RIPC;n=51),R-RIPC group(recipients received RIPC,n=51)and DR-RIPC group(both donors and recipients received RIPC;n=51).We primarily evaluated postoperative liver function among donors and recipients and incidences of early allograft dysfunction,primary nonfunction and postoperative complications among recipients.RESULTS RIPC did not significantly improve alanine transaminase and aspartate aminotransferase levels among donors and recipients or decrease the incidences of early allograft dysfunction,primary nonfunction,and postoperative complications among recipients.Limited protective effects were observed,including a lower creatinine level in the D-RIPC group than in the S-RIPC group on postoperative day 0(P<0.05).However,no significant improvements were found in donors who received RIPC.Furthermore,RIPC had no effects on the overall survival of recipients.CONCLUSION The protective effects of RIPC were limited for recipients who received living liver transplantation,and no significant improvement of the prognosis was observed in recipients.
基金supported by the National Natural Science Foundation of China (The mechanism of the remote ischemia postconditioning and its time therapeutic window), No.30870854(The cerebral protection of remote ischemia postconditioning and its mechanism), No. 30770743(The effect and its mechanism of EPO intravascular injection on the thrombolysis time window of tPA on cerebral infarction in rats),No. 81071058
文摘Three cycles of remote ischemic pre-conditioning induced by temporarily occluding the bilateral femoral arteries (10 minutes) prior to 10 minutes of reperfusion were given once a day for 3 days before the animal received middle artery occlusion and reperfusion surgery. The results showed that brain infarct volume was significantly reduced after remote ischemic pre-conditioning. Scores in the forelimb placing test and the postural reflex test were significantly lower in rats having undergone remote ischemic pre-conditioning compared with those who did not receive remote ischemic pre-conditioning. Thus, neurological function was better in rats having undergone remote ischemic pre-conditioning compared with those who did not receive remote ischemic pre-conditioning. These results indicate that remote ischemic pre-conditioning in rat hindlimb exerts protective effects in ischemia-reperfusion injury.
基金Supported by National Natural Science Foundation of China,No.81421062the Science and Technology Bureau of Zhejiang Province,China,No.2016C33145+1 种基金the National Natural Science Foundation of China,No.81470891the 863 National High Technology Research and Development Program of China for young scientist No.2015AA020923
文摘AIM To investigate the underlying mechanisms of the protective role of remote ischemic perconditioning(RIPerC) in rat liver transplantation. METHODS Sprague-Dawley rats were subjected to sham, orthotopic liver transplantation(OLT), ischemic postconditioning(IPostC) or RIPerC. After 3 h reperfusion, blood samples were taken for measurement of alanine aminotransferase, aspartate aminotransferase, creatinine(Cr) and creatinine kinase-myocardial band(CK-MB). The liver lobes were harvested for the following measurements: reactive oxygen species(ROS), H2O2, mitochondrial membrane potential(ΔΨm) and total nitric oxide(NO). These measurements were determined using an ROS/H2O2, JC1 and Total NOx Assay Kit, respectively. Endothelial NO synthase(e NOS) was analyzed by reverse transcription-polymerase chain reaction(RTPCR) and western blotting, and peroxynitrite was semiquantified by western blotting of 3-nitrotyrosine. RESULTS Compared with the OLT group, the grafts subjected to RIPerC showed significantly improved liver and remote organ functions(P < 0.05). ROS(P < 0.001) including H2O2(P < 0.05) were largely elevated in the OLT group as compared with the sham group, and RIPerC(P < 0.05) reversed this trend. The collapse of ΔΨm induced by OLT ischemia/reperfusion(I/R) injury was significantly attenuated in the RIPerC group(P < 0.001). A marked increase of NO content and phosphoserine eN OS, both in protein and mR NA levels, was observed in liver graft of the RIPer C group as compared with the OLT group(P < 0.05). I/R-induced 3-nitrotyrosine content was significantly reduced in the RIPerC group as compared with the OLT group(P < 0.05). There were no significant differences between the RIPerC and IPostC groups for all the results except Cr. The Cr level was lower in the RIPerC group than in the IPostC group(P < 0.01).CONCLUSION Liver graft protection by RIPerC is similar to or better than that of IPostC, and involves inhibition of oxidative stress and up-regulation of the PI3K/Akt/e NOS/NO pathway.
文摘Common gastrointestinal diseases such as radiation enteritis(RE),acute pancreatitis,inflammatory bowel diseases(IBD)and drug-induced hepatotoxicity share pathophysiological mechanisms at the molecular level,mostly involving the activation of many pathways of the immune response,ultimately leading to tissue injury.Increased oxidative stress,inflammatory cytokine release,inflammatory cell infiltration and activation and the up-regulation of inflammatory transcription factors participate in the pathophysiology of these complex entities.Treatment varies in each specific disease,but at least in the cases of RE and IBD immunosuppressors are effective.However,full therapeutic responses are not always achieved.The pathophysiology of ischemiareperfusion(IR)injury shares many of these mechanisms.Brief and repetitive periods of ischemia in an organ or limb have been shown to protect against subsequent major IR injury in distant organs,a phenomenon called remote ischemic preconditioning(RIP).This procedure has been shown to protect the gut,pancreas and liver by modulating many of the same inflammatory mechanisms.Since RIP is safe and tolerable,and has shown to be effective in some recent clinical trials,I suggest that RIP could be used as a physiologicallyrelevant adjunct treatment for non-ischemic gastrointestinal inflammatory conditions.
基金supported by the Natural Science Foundation(Joint Fund)of Liaoning Provincial Science and Technology Department,No.2013022021
文摘It is difficult to control the degree of ischemic postconditioning in the brain and other ischemia-sensitive organs.Remote ischemic postconditioning could protect some ischemia-sensitive organs through measures on terminal organs.In this study,a focal cerebral ischemia-reperfusion injury model was established using three cycles of remote ischemic postconditioning,each cycle consisted of 10-minute occlusion of the femoral artery and 10-minute opening.The results showed that,remote ischemic postconditioning significantly decreased the percentage of the infarct area and attenuated brain edema.In addition,inflammatory nuclear factor-κB expression was significantly lower,while anti-apoptotic Bcl-2 expression was significantly elevated in the cerebral cortex on the ischemic side.Our findings indicate that remote ischemic postconditioning attenuates focal cerebral ischemia/reperfusion injury,and that the neuroprotective mechanism is mediated by an anti-apoptotic effect and reduction of the inflammatory response.
基金Supported by Science and Technology Innovation Talents Support Plan,Department of Education,Henan Province,China,No.17HASTIT044China Postdoctoral Science Foundation,No.2017M610374
文摘AIM To investigate the protective mechanism of mitofusin-2(Mfn2) in rat remote ischemic perconditioning(RIC) models and revalidate it in alpha mouse liver-12(AML-12) hypoxia cell lines.METHODS Sprague-Dawley rats were divided into three groups(n = 6 each): sham, orthotopic liver transplantation and RIC. After operation, blood samples were collected to test alanine aminotransferase and aspartate aminotransferase. The liver lobes were harvested for histopathological examination, western blotting(WB) and quantitative real-time(q RT)-PCR. AML-12 cell lines were then subjected to normal culture, anoxic incubator tank culture(hypoxia) and anoxic incubator tank culture with Mfn2 knockdown(hypoxia + Si), and data of q RT-PCR, WB, mitochondrial membrane potential(ΔΨm), apoptosis, endoplasmic reticulum Ca2+ concentrations and mitochondrial Ca2+ concentrations were collected.RESULTS Both sham and normal culture groups showed no injury during the experiment. The RIC group showed amelioration of liver function compared with the orthotopic liver transplantation group(P < 0.05). q RTPCR and WB confirmed that Mfn2-mitochondrial Ca2+ uptake 1/2(MICUs) axis was changed(P < 0.005). In AML-12 cell lines, compared with the hypoxia group, the hypoxia + Si group attenuated the collapse of ΔΨm and apoptosis(P < 0.005). The endoplasmic reticulum Ca2+ decrease and mitochondrial Ca2+ overloading observed in the hypoxia group were also attenuated in the hypoxia + Si group(P < 0.005). Finally, q RT-PCR and WB confirmed the Mfn2-MICUs axis change in all the groups(P < 0.005).CONCLUSION Mfn2 participates in liver injury in rat RIC models and AML-12 hypoxia cell lines by regulating the MICUs pathway.
基金Supported by Science Fund of the Department for General and Visceral Surgery at the University of Freiburg
文摘AIM: To investigate the influence of remote ischemic preconditioning (RIPC) on anastomotic integrity. METHODS: Sixty male Wistar rats were randomized to six groups. The control group (n = 10) had an end-to-end ileal anastomosis without RIPC. The preconditioned groups (n = 34) varied in time of ischemia and time of reperfusion. One group received the amino acid L-arginine before constructing the anastomosis (n = 9). On postoperative day 4, the rats were re-laparotomized, and bursting pressure, hydroxyproline concentration, intra-abdominal adhesions, and a histological score concerning the mucosal ischemic injury were collected. The data are given as median (range).RESULTS: On postoperative day 4, median bursting pressure was 124 mmHg (60-146 mmHg) in the control group. The experimental groups did not show a statistically significant difference (P > 0.05). Regarding the hydroxyproline concentration, we did not find any significant variation in the experimental groups. We detected significantly less mucosal injury in the RIPC groups. Furthermore, we assessed more extensive intra-abdominal adhesions in the preconditioned groups than in the control group. CONCLUSION: RIPC directly before performing small bowel anastomosis does not affect anastomotic stability in the early period, as seen in ischemic preconditioning.
文摘AIM To study whether remote ischemic preconditioning(RIPC) has an impact on clinical outcomes, such as post-operative atrial fibrillation(POAF).METHODS This was a prospective, single-center, single-blinded,randomized controlled study. One hundred and two patients were randomized to receive RIPC(3 cycles of 5 min ischemia and 5 min reperfusion in the upper arm after induction of anesthesia) or no RIPC(control). Primary outcome was POAF lasting for five minutes or longer during the first seven days after surgery. Secondary outcomes included length of hospital stay, incidence of inpatient mortality, myocardial infarction, and stroke. RESULTS POAF occurred at a rate of 54% in the RIPC group and 41.2% in the control group(P = 0.23). No statistically significant differences were noted in secondary outcomes between the two groups. CONCLUSION This is the first study in the United States to suggest that RIPC does not reduce POAF in patients with elective or urgent cardiac surgery. There were no differences in adverse effects in either group. Further studies are required to assess the relationship between RIPC and POAF.
基金supported by the National Natural Science Foundation of China,No.30960107the Natural Science Foundation of the Education Department of Sichuan Province of China,No.14ZA0223
文摘Integrity of the blood-brain barrier structure is essential for maintaining the internal environment of the brain.Development of cerebral infarction and brain edema is strongly associated with blood-brain barrier leakage.Therefore,studies have suggested that protecting the blood-brain barrier may be an effective method for treating acute stroke.To examine this possibility,stroke model rats were established by middle cerebral artery occlusion and reperfusion.Remote ischemic postconditioning was immediately induced by three cycles of 10-minute ischemia/10-minute reperfusion of bilateral hind limbs at the beginning of middle cerebral artery occlusion reperfusion.Neurological function of rat models was evaluated using Zea Longa's method.Permeability of the blood-brain barrier was assessed by Evans blue leakage.Infarct volume and brain edema were evaluated using 2,3,5-triphenyltetrazolium chloride staining.Expression of matrix metalloproteinase-9 and claudin-5 m RNA was determined by real-time quantitative reverse transcription-polymerase chain reaction.Expression of matrix metalloproteinase-9 and claudin-5 protein was measured by western blot assay.The number of matrix metalloproteinase-9-and claudin-5-positive cells was analyzed using immunohistochemistry.Our results showed that remote ischemic postconditioning alleviated disruption of the blood-brain barrier,reduced infarct volume and edema,decreased expression of matrix metalloproteinase-9 m RNA and protein and the number of positive cells,increased expression of claudin-5 m RNA and protein and the number of positive cells,and remarkably improved neurological function.These findings confirm that by suppressing expression of matrix metalloproteinase-9 and claudin-5 induced by acute ischemia/reperfusion,remote ischemic postconditioning reduces blood-brain barrier injury,mitigates ischemic injury,and exerts protective effects on the brain.
基金supported by a grant from 2013 Applied Basic Research of Changzhou Bureau of Science and Technology(CJ20130044)
文摘BACKGROUND:Ischemic preconditioning(IPC) is a strategy to reduce ischemia-reperfusion(I/R) injury.The protective effect of remote ischemic preconditioning(RIPC) on liver I/R injury is not clear.This study aimed to investigate the roles of RIPC in liver I/R in fatty liver rats and the involvement of endothelial nitric oxide synthase-nitric oxide(eNOS-NO) pathway and microRNA expressions in this process.METHODS:A total of 32 fatty rats were randomly divided into the sham group,I/R group,RIPC group and RIPC+I/R group.Serum alanine aminotransferase(ALT),aspartate aminotransferase(AST) and nitric oxide(NO) were measured.Hematoxylin-eosin staining was used to observe histological changes of liver tissues,TUNEL to detect hepatocyte apoptosis,and immunohistochemistry assay to detect heat shock protein 70(HSP70) expression.Western blotting was used to detect liver inducibleNOS(iNOS) and eNOS protein levels and realtime quantitative polymerase chain reaction to detect miR-34a,miR-122 and miR-27b expressions.RESULTS:Compared with the sham and RIPC groups,serum ALT,AST and iNOS in liver tissue were significantly higher in other two groups,while serum NO and eNOS in liver tissue were lower,and varying degrees of edema,degeneration and inflammatory cell infiltration were found.Cell apoptosis number was slightly lower in the RIPC+I/R group than that in I/R group.Compared with the sham group,HSP70 expressions were significantly increased in other three groups(all P<0.05).Compared with the sham and RIPC groups,elevated miR-34a expressions were found in I/R and RIPC+I/R groups(P<0.05).MiR-122 and miR-27b were found significantly decreased in I/R and RIPC+I/R groups compared with the sham and RIPC groups(all P<0.05).CONCLUSION:RIPC can reduce fatty liver I/R injury by affecting the eNOS-NO pathway and liver microRNA expressions.
文摘Despite obvious progress in the treatment of acute forms of ischemic stroke, the risk of this condition remains unacceptably high. Brain infarction in the middle cerebral artery basin occurs in patients with atherosclerosis. The onset of the brain infarction is facilitated by the cessation of circulation (embolism) in conditions of insufficient collateral circulation. The extent of the infarct zone is determined by neuronal death and impaired microcirculation. The development of new methods for effective targeted restorative stroke therapy is crucial for restorative treatment and reducing the risk of mortality after stroke. Remote ischemic conditioning (RIC) is an approach to limiting reperfusion injury in the ischemic region of the brain after focal ischemia. One of the most commonly used <i>in vivo</i> models in stroke studies is the filament model of Middle Cerebral Artery Occlusion (MCAO) in rats. In our experiment, it was performed for 30 min (J. Koizumi) with subsequent 48-hour reperfusion. Within the first 24 hours after the start of reperfusion several short episodes of ischemia in low limbs were induced. After 48 hours of reperfusion the brains were harvested and stained with TTC. Then we evaluated the effect of RIC within 24 hours <i>ex vivo</i> in rats’ brains, as well as syndecan-1 plasma concentration. Infarct area was assessed by means of Image-Pro program with statistical analysis. Infarct volumes in the model group (31.97% ± 2.5%) were significantly higher compared to the values in the RIC group 48 hours after ischemia-reperfusion (13.6% ± 1.3%) (*P < 0.05). A significant reduction in the area of infarction after RIC is likely due to the effect on the regulation of collateral blood flow in the ischemia area. On the second day after ischemia-reperfusion, tissue swelling was reduced in the RIC group compared to the model group. Analysis of the average concentration of Syndecan-1 revealed the difference between model and RIC groups. Syndecan-1, endothelial glycocalyx protein, might be the regulator which performs vascular control of the interaction with inflammatory cell and is responsible for mediate effect of remote ischemic conditioning on the restriction of ischemic-reperfusion injury.
文摘Ischemic stroke is a major neurological disease with limited effective therapeutic options except for thrombolysis and thrombectomy. Remote ischemic conditioning (RIC) is an approach that promises an alternative to the current treatment portfolio. As an easy-handled, non-invasive regimen, it takes advantage of transient ischemia (currently often made through inflation and deflation of limb blood pressure cuff) to enhance the tolerance of vital organs to ischemia. RIC can be executed before, during and after the onset of stroke. The mechanisms of action of RIC employed at different stroke stages are similar and may involve humoral, neurological and inflammatory pathways. As new mechanisms underlying RIC-induced neuroprotection continue to be revealed, we review in this article some of the latest development in this field, including:① RIC and RIC-induced fundamental change, hypoxia, as well as the role of hypoxia inducible factors against stroke;② Potential role of RIC-induced extracellular vesicles in neuroprotection;③ RIC-induced metabolic changes in tissue protection;④ Potential effect of RIC on red blood cells (RBC) oxygen delivery;and ⑤ RIC and its anti-inflammatory potential.
文摘Acute myocardial infarction initiates a cascade of events including loss of protein homeostasis and chronic inflammation that affect overall cellular repair and senescence. This contributes to loss of cardiomyocytes and consequent formation of fibrotic scar. In certain vertebrate species, the heart can completely self-repair or regenerate after myocardial injury;however, this does not appear to be the case for humans. Despite this limitation, studies using novel non-pharmacologic interventions designed to protect against ischemic damage and to improve patient outcomes are ongoing. Remote ischemic conditioning stratagems are used to attenuate ischemia-reperfusion injury in clinical and animal studies;endogenous protective factors that stimulate complex signal transduction pathways are deemed responsible. Some of these factors could conceivably act in concert with those involved in regulating cardiovascular regeneration. Numerous studies have focused on cardiac regenerative interventions using stem-cell based therapies and transplantation of cardiomyocyte (or other cell types) or biocompatible matrices. This review discusses recent progress of pre-clinical and clinical translational studies for cardiac regeneration. In addition, we submit that interventions using cellular adjunctive therapies combined with remote ischemic conditioning may prove to be of interest in the battle to find novel strategies for protection against cardiac injury.
基金supported by the National Key R&D Program of China(2017YFC1308400)the National Natural Science Foundation(81371289)+1 种基金and the Beijing Natural Science Foundation(7212047)and Capital Medical Development Scientific Research Fund(2022-2-2015).
文摘Background: Long-term remote ischemic conditioning (RIC) has been proven to be beneficial in multiple diseases, such as cerebral and cardiovascular diseases. However, the hyperacute and acute effects of a single RIC stimulus are still not clear. Quantitative proteomic analyses of plasma proteins following RIC application have been conducted in preclinical and clinical studies but exhibit high heterogeneity in results due to wide variations in experimental setups and sampling procedures. Hence, this study aimed to explore the immediate effects of RIC on plasma proteome in healthy young adults to exclude confounding factors of disease entity, such as medications and gender. Methods: Young healthy male participants were enrolled after a systematic physical examination and 6-month lifestyle observation. Individual RIC sessions included five cycles of alternative ischemia and reperfusion, each lasting for 5 min in bilateral forearms. Blood samples were collected at baseline, 5 min after RIC, and 2 h after RIC, and then samples were processed for proteomic analysis using liquid chromatography-tandem mass spectrometry method. Results: Proteins related to lipid metabolism (e.g., Apolipoprotein F), coagulation factors (hepatocyte growth factor activator preproprotein), members of complement cascades (mannan-binding lectin serine protease 1 isoform 2 precursor), and inflammatory responses (carboxypeptidase N catalytic chain precursor) were differentially altered at their serum levels following the RIC intervention. The most enriched pathways were protein glycosylation and complement/coagulation cascades. Conclusions: One-time RIC stimulus may induce instant cellular responses like anti-inflammation, coagulation, and fibrinolysis balancing, and lipid metabolism regulation which are protective in different perspectives. Protective effects of single RIC in hyperacute and acute phases may be exploited in clinical emergency settings due to apparently beneficial alterations in plasma proteome profile. Furthermore, the beneficial effects of long-term (repeated) RIC interventions in preventing chronic cardiovascular diseases among general populations can also be expected based on our study findings.
基金supported by grants from the National Institutes of Health (NIHR01 HL091478) for W.Keith Jonesthe National Natural Science Foundation of China (81470425) for Xiaoping Ren
文摘Ac ute myocardial infarction(AMI) is the leading cause of death and disability worldwide. Timely reperfusion is the standard of care and results in decreased infarct size, improving patient survival and prognosis. However, 25% of patients proceed to develop heart failure(HF) after myocardial infarction(MI) and 50% of these will die within fi ve years. Since the size of the infarct is the major predictor of the outcome, including the development of HF, therapies to improve myocardial salvage have great potential. Over the past three decades, a number of stimuli have been discovered that activate endogenous cardioprotective pathways. In ischemic preconditioning(IPC) and ischemic postconditioning, ischemia within the heart initiates the protection. Brief reversible episodes of ischemia in vascular beds remote from the heart can also trigger cardioprotection when applied before, during, or immediately after myocardial ischemia—known as remote ischemic pre-, per-, and post-conditioning, respectively. Although the mechanism of remote ischemic preconditioning(RIPC) has not yet been fully elucidated, many mechanistic components are shared with IPC. The discovery of RIPC led to research into the use of remote non-ischemic stimuli including nerve stimulation(spinal and vagal), and electroacupuncture(EA). We discovered and, with others, have elucidated mechanistic aspects of a nonischemic phenomenon we termed remote preconditioning of trauma(RPCT). RPCT operates via neural stimulation of skin sensory nerves and has similarities and differences to nerve stimulation and EA conducted at acupoints. We show herein that RPCT can be mimicked using electrical stimulation of the abdominal midline(EA-like treatment) and that this modality of activating cardioprotection is powerful as both a preconditioning and a postconditioning stimulus(when applied at reperfusion). Investigations of these cardioprotective phenomena have led to a more integrative understanding of mechanisms related to cardioprotection, and in the last five to ten years, it has become clear that the mechanisms aresimilar, whether induced by ischemic or non-ischemic stimuli. Taking together much of the data in the literature, we propose that all of these cardioprotective "conditioning" phenomena represent activation from different entry points of a cardiac conditioning network that converges upon specifi c mediators and effectors of myocardial cell survival, including NF-κB, Stat3/5, protein kinase C, bradykinin, and the mi to K ATP channel. Nervous system pathways may represent a novel mechanism for initiating conditioning of the heart and other organs. IPC and RIPC have proven difficult to translate clinically, as they have associated risks and cannot be used in some patients. Because of this, the use of neural and nociceptive stimuli is emerging as a potential non-ischemic and non-traumatic means to initiate cardiac conditioning. Clinical relevance is underscored by the demonstration of postconditioning with one of these modalities, supporting the conclusion that the development of pharmaceuticals and electroceuticals for this purpose is an area ripe for clinical development.
