In this editorial,we comment on the article published in the recent issue of the World Journal of Stem Cells.They focus on stem cell preconditioning to prevent ferroptosis by modulating the cystathionineγ-lyase/hydro...In this editorial,we comment on the article published in the recent issue of the World Journal of Stem Cells.They focus on stem cell preconditioning to prevent ferroptosis by modulating the cystathionineγ-lyase/hydrogen sulfide(H_(2)S)pathway as a novel approach to treat vascular disorders,particularly pulmonary hypertension.Preconditioned stem cells are gaining popularity in regenerative medicine due to their unique ability to survive by resisting the harsh,unfavorable microenvironment of the injured tissue.They also secrete various paracrine factors against apoptosis,necrosis,and ferroptosis to enhance cell survival.Ferroptosis,a regulated form of cell death characterized by iron accumulation and oxidative stress,has been implicated in various pathologies encompassing dege-nerative disorders to cancer.The lipid peroxidation cascade initiates and sustains ferroptosis,generating many reactive oxygen species that attack and damage multiple cellular structures.Understanding these intertwined mechanisms provi-des significant insights into developing therapeutic modalities for ferroptosis-related diseases.This editorial primarily discusses stem cell preconditioning in modulating ferroptosis,focusing on the cystathionase gamma/H_(2)S ferroptosis pathway.Ferroptosis presents a significant challenge in mesenchymal stem cell(MSC)-based therapies;hence,the emerging role of H_(2)S/cystathionase gamma/H_(2) S signaling in abrogating ferroptosis provides a novel option for therapeutic intervention.Further research into understanding the precise mechanisms of H_(2)S-mediated cytoprotection against ferroptosis is warranted to enhance the thera-peutic potential of MSCs in clinical settings,particularly vascular disorders.展开更多
BACKGROUND Mesenchymal stem cells(MSCs)have great potential for the treatment of various immune diseases due to their unique immunomodulatory properties.However,MSCs exposed to the harsh inflammatory environment of da...BACKGROUND Mesenchymal stem cells(MSCs)have great potential for the treatment of various immune diseases due to their unique immunomodulatory properties.However,MSCs exposed to the harsh inflammatory environment of damaged tissue after intravenous transplantation cannot exert their biological effects,and therefore,their therapeutic efficacy is reduced.In this challenging context,an in vitro preconditioning method is necessary for the development of MSC-based therapies with increased immunomodulatory capacity and transplantation efficacy.AIM To determine whether hypoxia and inflammatory factor preconditioning increases the immunosuppressive properties of MSCs without affecting their biological characteristics.METHODS Umbilical cord MSCs(UC-MSCs)were pretreated with hypoxia(2%O_(2))exposure and inflammatory factors(interleukin-1β,tumor necrosis factor-α,interferon-γ)for 24 h.Flow cytometry,polymerase chain reaction,enzyme-linked immunosorbent assay and other experimental methods were used to evaluate the biological characteristics of pretreated UC-MSCs and to determine whether pretreatment affected the immunosuppressive ability of UC-MSCs in coculture with immune cells.RESULTS Pretreatment with hypoxia and inflammatory factors caused UC-MSCs to be elongated but did not affect their viability,proliferation or size.In addition,pretreatment significantly decreased the expression of coagulationrelated tissue factors but did not affect the expression of other surface markers.Similarly,mitochondrial function and integrity were retained.Although pretreatment promoted UC-MSC apoptosis and senescence,it increased the expression of genes and proteins related to immune regulation.Pretreatment increased peripheral blood mononuclear cell and natural killer(NK)cell proliferation rates and inhibited NK cell-induced toxicity to varying degrees.CONCLUSION In summary,hypoxia and inflammatory factor preconditioning led to higher immunosuppressive effects of MSCs without damaging their biological characteristics.展开更多
AIM:To study the effects of preconditioning on inducible nitric oxide synthase(iNOS)and interleukin 1(IL-1)receptor transcription in rat liver ischemia/reperfusion injury(IRI).METHODS:Seventy-two male rats were random...AIM:To study the effects of preconditioning on inducible nitric oxide synthase(iNOS)and interleukin 1(IL-1)receptor transcription in rat liver ischemia/reperfusion injury(IRI).METHODS:Seventy-two male rats were randomized into 3 groups:the one-hour segmental ischemia(IRI,n=24)group,the ischemic preconditioning(IPC,n=24)group or the remote ischemic preconditioning(RIPC,n=24)group.The IPC and R-IPC were performed as 10 min of ischemia and 10 min of reperfusion.The iNOS and the IL-1 receptor mRNA in the liver tissue was analyzed with real time PCR.The total Nitrite and Nitrate(NOx)in continuously sampled microdialysate(MD)from the liver was analyzed.In addition,the NOx levels in the serum were analyzed.RESULTS:After 4 h of reperfusion,the iNOS mRNA was significantly higher in the R-IPC(ΔCt:3.44±0.57)group than in the IPC(ΔCt:5.86±0.82)group(P=0.025).The IL-1 receptor transcription activity was reduced in the IPC group(ΔCt:1.88±0.53 to 4.81±0.21),but not in the R-IPC group,during reperfusion(P=0.027).In the MD,a significant drop in the NOx levels was noted in the R-IPC group(12.3±2.2 to 4.7±1.2μmol/L)at the end of ischemia compared with the levels in early ischemia(P=0.008).A similar trend was observed in the IPC group(11.8±2.1 to 6.4±1.5μmol/L),although this difference was not statistically significant.The levels of NOx rose quickly during reperfusion in both groups.CONCLUSION:IPC,but not R-IPC,reduces iNOS and IL-1 receptor transcription during early reperfusion,indicating a lower inflammatory reaction.NOx is consumed in the ischemic liver lobe.展开更多
BACKGROUND:Hepatocyte apoptosis is a severe form of cell death after hepatic ischemia-reperfusion injury(HIRI), and its relief is an important issue in liver transplantation. Hypoxic preconditioning(HP)is considered t...BACKGROUND:Hepatocyte apoptosis is a severe form of cell death after hepatic ischemia-reperfusion injury(HIRI), and its relief is an important issue in liver transplantation. Hypoxic preconditioning(HP)is considered to have protective effects on HIRI.This study was designed to explore the impact of HP on apoptosis and its possible mechanism during orthotopic liver autotransplantation. METHODS:A modified orthotopic liver autotransplantation model was used to simulate HIRI.Sprague-Dawley rats were randomly divided into normal control,autotransplantation (AT)and HP groups.The HP group was subjected to an 8%oxygen atmosphere for 90 minutes before surgery.At 1,6 and 24 hours after surgery,the rats were killed and their liver tissue was sampled to assess the expression of Bcl-2 protein.The samples were subjected to blood chemistry study,morphological study under a light or transmission electron microscope,and quantitative study of mitochondria. RESULTS:The serum levels of ALT and AST in the HP group were lower than those in the AT group at 1,6 and 24 hours after orthotopic liver autotransplantation(P<0.05).Bcl-2 protein expression was increased in the HP group at each measurement point(P<0.05).Light microscopy showed that hepatic injury in the AT group was much more severe than in the HP group.Hepatocytes in the AT group showed typical apoptosis signs under a transmission electron microscope.The ultrastructural appearance of hepatocytes in the HP group was much better than in the AT group,and the area,perimeter and diameter of the mitochondria were smaller in the HP group than in the AT group(P<0.05). CONCLUSIONS:Hepatocytes sense and respond to decreased tissue oxygenation.Stimulation by HP relieves apoptosis by upregulating expression of Bcl-2 protein and its protection of mitochondria after orthotopic liver autotransplantation.展开更多
BACKGROUND:Ischemia-reperfusion injury occurs when ischemic tissues or organs suffer from further functional and structural damage when their blood supply recovers.This study aimed to contrast the protective effects o...BACKGROUND:Ischemia-reperfusion injury occurs when ischemic tissues or organs suffer from further functional and structural damage when their blood supply recovers.This study aimed to contrast the protective effects of ischemic preconditioning and ischemic postconditioning in hepatic ischemia-reperfusion injury in rats.METHODS:Thirty-two healthy male Wistar rats were randomly divided into four groups:sham-operated(SO),ischemia-reperfusion(IR),ischemic preconditioning(I-pre),and ischemic postconditioning(I-post).Blood samples and hepatic tissue were taken from all groups after the experiments.RESULTS:There were significant differences between the IR,I-pre and I-post groups in alanine aminotransferase and aspartate aminotransferase levels,NF-κB p65 expression,apoptosis index and superoxide dismutase activity in hepatic tissue.There were no significant differences between the I-pre and I-post groups.CONCLUSIONS:Ischemic postconditioning and ischemic preconditioning reduce hepatic ischemia-reperfusion injury,but in clinical practice the former is a more appropriate choice.展开更多
AIM:To characterize the impact of the Pringle ma-neuver (PM) and ischemic preconditioning (IP) on total blood supply to the liver following hepatectomies. METHODS: Sixty one consecutive patients who un-derwent hepatic...AIM:To characterize the impact of the Pringle ma-neuver (PM) and ischemic preconditioning (IP) on total blood supply to the liver following hepatectomies. METHODS: Sixty one consecutive patients who un-derwent hepatic resection under in flow occlusion were randomized either to receive PM alone (n = 31) or IP (10 min of ischemia followed by 10 min of reperfusion) prior to PM (n = 30). Quantification of liver perfusion was measured by Doppler probes at the hepatic artery and portal vein at various time points after reperfusion of remnant livers. RESULTS: Occlusion times of 33 ± 12 min (mean ± SD) and 34 ± 14 min and the extent of resected liver tissue (2.7 segments) were similar in both groups. In controls (PM), on reperfusion of liver remnants for 15 min, portal perfusion markedly decreased by 29% while there was a slight increase of 8% in the arterial blood flow. In contrast, following IP + PM the portal vein flow remained unchanged during reperfusion and a significantly increased arterial blood flow (+56% vs baseline) was observed. In accordance with a better postischemic blood supply of the liver, hepatocellular injury, as measured by alanine aminotransferase (ALT) levels on day 1 was considerably lower in group B compared to group A (247 ± 210 U/I vs 550 ± 650 U/I, P < 0.05). Additionally, ALT levels were significantly correlated to the hepatic artery in flow.CONCLUSION: IP prevents postischemic flow reduction of the portal vein and simultaneously increases arterial perfusion, suggesting that improved hepatic macrocirculation is a protective mechanism following hepatectomy.展开更多
BACKGROUND: Ischemia/reperfusion is the main cause of hepatic damage in liver transplantation. Immediate early genes (IEGs) encode proteins can regulate expression of cellular response genes after injury, and is assoc...BACKGROUND: Ischemia/reperfusion is the main cause of hepatic damage in liver transplantation. Immediate early genes (IEGs) encode proteins can regulate expression of cellular response genes after injury, and is associated with tissue repair and cell apoptosis. The purpose of this re- search was to investigate the effects of preconditioning on expression of immediate early genes c-fos and c-jun follow- ing hepatic ischemia/reperfusion (IR) and its roles in cellu- lar regeneration and apoptosis. METHODS: Ninety-six Wistar rats were randomly divided into IR group and hepatic ischemic preconditioning (IPC) group, and each group was further divided into eight sub- groups (n =6). The model of partial liver ischemia/reper- fusion was used. The rats were subjected to 60-minute liver ischemia, preceded by 10-minute preconditioning. After 0-, 0.5-, 1-, 2-, 4-, 8-, 12-, 24-hour reperfusion, the se- rum and liver tissue in each group were collected to detect the level of serum ALT/AST, liver histopathology, expres- sion of c-fos, and c-jun mRNA. Flow cytometer was used to detect Ki67 and Sub-G1 as the quantity indicators of cell regeneration and apoptosis respectively. RESULTS: Compared with IR group, IPC group showed a significantly lower ALT/AST level in 0. 5-hour sub-group to 8-hour sub-group (P<0.05). Ki67 elevated significantly at 0.5, 1, 2 hours, but decreased significantly at 24 hours ( P < 0 . 05). Ap index decreased significantly after 1-hour reperfusion(P<0.05). Expressions of c-fos and c-jun mR- NA were low, especially c-jun at 0.5, 1 and 2 hours after reperfusion. CONCLUSION: Ischemic preconditioning can protect liver cells against ischemia/reperfusion injury, and this protec- tive effect may be related to influence transcription levels of c-fos and c-jun.展开更多
BACKGROUND: Liver transplantation is so far the most effective therapeutic modality for end-stage liver diseases, but ischemia/reperfusion (I/R) injury represents a critical barrier to liver transplantation. Primary g...BACKGROUND: Liver transplantation is so far the most effective therapeutic modality for end-stage liver diseases, but ischemia/reperfusion (I/R) injury represents a critical barrier to liver transplantation. Primary graft dysfunction and small-for-size syndrome are closely associated with I/R injury. Ischemic preconditioning (IPC) is defined as a brief period of liver ischemia followed by reperfusion, and has demonstrated protections against a prolonged I/R injury and improved the capacity of regeneration. The article aimed to review IPC literatures for the understanding of the effects of IPC on I/R injury involving in the procurement of donor liver and protective mechanisms. DATA SOURCES: A literature search of MEDLINE and Web of Science databases using "liver transplantation", "liver regeneration", "hepatectomy", "ischemia/reperfusion" and "ischemic preconditioning" was performed, and then a large amount of related data was collected. RESULTS: The literature search provided a huge amount of evidence for the protective effects of IPC on I/R injury in liver transplantation, including reduction of blood loss in hepatectomy, intraoperative hemodynamic stability and its significant role in liver regeneration. The mechanism involves in balancing inflammatory cytokines, enhancing energy status and mitigating microcirculatory disturbance.CONCLUSION: IPC plays an essential role in hepatectomy before and after harvest of living donor liver and implantation of liver graft.展开更多
Hypoxic preconditioning can protect against cerebral ischemia/reperfusion injury. However, the underlying mechanisms that mediate this effect are not completely clear. In this study, mice were pretreated with continuo...Hypoxic preconditioning can protect against cerebral ischemia/reperfusion injury. However, the underlying mechanisms that mediate this effect are not completely clear. In this study, mice were pretreated with continuous, intermittent hypoxic preconditioning;1 hour later, cerebral ischemia/reperfusion models were generated by middle cerebral artery occlusion and reperfusion. Compared with control mice, mice with cerebral ischemia/reperfusion injury showed increased Bederson neurological function scores, significantly increased cerebral infarction volume, obvious pathological damage to the hippocampus, significantly increased apoptosis;upregulated interleukin-1β, interleukin-6, and interleukin-8 levels in brain tissue;and increased expression levels of NOD-like receptor family pyrin domain containing 3(NLRP3), NLRP inflammasome-related protein caspase-1, and gasdermin D. However, hypoxic preconditioning significantly inhibited the above phenomena. Taken together, these data suggest that hypoxic preconditioning mitigates cerebral ischemia/reperfusion injury in mice by reducing NLRP3 inflammasome expression. This study was approved by the Medical Ethics Committee of the Fourth Hospital of Baotou, China(approval No. DWLL2019001) in November 2019.展开更多
AIM: To evaluate preventative effects of ischemic preconditioning(IP) in a rat model of intestinal injury induced by ischemia-reperfusion(IR).METHODS: Male Sprague-Dawley rats(250-300 g) were fasted for 24 h with free...AIM: To evaluate preventative effects of ischemic preconditioning(IP) in a rat model of intestinal injury induced by ischemia-reperfusion(IR).METHODS: Male Sprague-Dawley rats(250-300 g) were fasted for 24 h with free access to water prior to the operation.Eighteen rats were randomly divided into three experimental groups: S group(n = 6),rats were subjected to isolation of the superior mesenteric artery(SMA) for 40 min,then the abdomen was closed; IRgroup(n = 6),rats were subjected to clamping the SMA 40 min,and the abdomen was closed followed by a 4-h reperfusion; IP group(n = 6) rats underwent three cycles of 5 min ischemia and 5 min reperfusion,then clamping of the SMA for 40 min,then the abdomen was closed and a 4-h reperfusion followed.All animals were euthanized by barbiturate overdose(150 mg/kg pentobarbital sodium,i.v.) for tissue collection,and the SMA was isolated via median abdominal incision.Intestinal histologic injury was observed.Malondialdehyde(MDA),myeloperoxidase(MPO) and tumor necrosis factor(TNF)-a concentrations in intestinal tissue were measured.Intercellular adhesion molecule(ICAM)-1 and vascular cell adhesion molecule(VCAM)-1 expression,as well as nuclear factor(NF)-κB activity and expression in intestinal tissue were also determined.RESULTS: Compared with the IR group,IP reduced IR-induced histologic injury of the intestine in rats(2.00 ± 0.71 vs 3.60 ± 0.84,P < 0.05).IP significantly inhibited the increase in MDA content(5.6 ± 0.15 μmol/L vs 6.84 ± 0.18 μmol/L,P < 0.01),MPO activity(0.13 ± 0.01 U/L vs 0.24 ± 0.01 U/L,P < 0.01),and TNF-a levels(7.79 ± 2.35 pg/m L vs 10.87 ± 2.48 pg/m L,P < 0.05) in the intestinal tissue of rats.IP also markedly ameliorated the increase in ICAM-1(204.67 ± 53.27 vs 353.33 ± 45.19,P < 0.05) and VCAM-1(256.67 ± 58.59 vs 377.33 ± 41.42,P < 0.05) protein expression in the intestinal tissues.Additionally,IP remarkably decreased NF-κB activity(0.48 ± 0.16 vs 0.76 ± 0.22,P < 0.05) and protein expression(320.23 ± 38.16 vs 520.76 ± 40.53,P < 0.01) in rat intestinal tissue.CONCLUSION: IP may protect against IR-induced intestinal injury by attenuation of the neutrophilendothelial adhesion cascade via reducing ICAM-1 and VCAM-1 expression and TNF-a-induced NF-κB signaling pathway activity.展开更多
BACKGROUND: Ischemic preconditioning(IPC) has been shown to decrease liver injury and to increase hepatic microvascular perfusion after liver ischemia reperfusion. This study aimed to evaluate the effects of IPC on he...BACKGROUND: Ischemic preconditioning(IPC) has been shown to decrease liver injury and to increase hepatic microvascular perfusion after liver ischemia reperfusion. This study aimed to evaluate the effects of IPC on hemodynamics of the portal venous system. METHODS: Thirty-two rats were randomized into two groups: IPC group and control group. The rats of the IPC group underwent IPC by 10 minutes of liver ischemia followed by 10 minutes of reperfusion before liver ischemia, and the rats of the control group were subjected to 60 minutes of partial liver ischemia. Non-ischemic lobes were resected immediately after reperfusion. The animals were studied at 4 hours and 12 hours after reperfusion. Mean arterial pressure, heart rate, portal vein flow and pressure were analyzed. Blood was collected for the determination of the levels of aspartate aminotransferase, alanine aminotransferase, calcium, lactate, pH, bicarbonate, and base excess. RESULTS: IPC increased the mean portal vein flow at 4 hours and 12 hours after reperfusion. IPC recovered 78% of the meanportal vein flow at 12 hours after reperfusion. IPC decreased the levels of aspartate aminotransferase, alanine aminotransferase and lactate, and increased the levels of ionized calcium, bicarbonate and base excess at 12 hours after reperfusion. CONCLUSIONS: This study demonstrated that IPC increases portal vein flow and enhances hepatoprotective effects in liver ischemia reperfusion. The better recovery of portal vein flow after IPC may be correlated with the lower levels of transaminases and with the better metabolic profile.展开更多
AIM:To investigate the effect of repeated lower +Gzexposure on liver injury induced by high +Gz exposure in rats.METHODS:Sixty male Wister rats were randomly divided into a blank control group,a low G preconditioning ...AIM:To investigate the effect of repeated lower +Gzexposure on liver injury induced by high +Gz exposure in rats.METHODS:Sixty male Wister rats were randomly divided into a blank control group,a low G preconditioning group(LG)(exposed to +4 Gz/5 min per day for 3 d before +10 Gz/5 min exposure),and a +10 Gz/5 min group(10G)(n = 20 in each group).Blood specimens and liver tissue were harvested at 0 h and 6 h after +10 Gz/5 min exposure.Liver function was analyzed by measuring serum alanine transaminase(ALT) and aspartate aminotransferase(AST) levels,and liver injury was further assessed by histopathological observation.Malondialdehyde(MDA),superoxide dismutase(SOD) and Na+-K+-ATPase were determined in hepatic tissue.RESULTS:The group LG had lower ALT,AST,and MDA values at 0 h after exposure than those in group 10 G.SOD values and Na+-K+-ATPase activity in the LG group were higher than in group 10 G 0 h post-exposure.Hepatocyte injury was significantly less in group LG than in group 10 G on histopathological evaluation.CONCLUSION:It is suggested that repeated low +Gz exposure shows a protective effect on liver injury induced by high +Gz exposure in rats.展开更多
Ischemia/reperfusion (I/R) injury still represents an important cause of morbidity following hepatic surgery and limits the use of marginal livers in hepatic transplantation. Transient blood flow interruption followed...Ischemia/reperfusion (I/R) injury still represents an important cause of morbidity following hepatic surgery and limits the use of marginal livers in hepatic transplantation. Transient blood flow interruption followed by reperfusion protects tissues against damage induced by subsequent I/R. This process known as ischemic pre-conditioning (IP) depends upon intrinsic cytoprotective systems whose activation can inhibit the progression of irreversible tissue damage. Compared to other organs,liver IP has additional features as it reduces inflammation and promotes hepatic regeneration. Our present understanding of the molecular mechanisms involved in liver IP is still largely incomplete. Experimental studies have shown that the protective effects of liver IP are triggered by the release of adenosine and nitric oxide and the subsequent activation of signal networks involving protein kinases such as phosphatidylinositol 3-kinase,protein kinase C δ/ε and p38 MAP kinase,and transcription factors such as signal transducer and activator of transcription 3,nuclear factor-κB and hypoxia-inducible factor 1. This article offers an overview of the molecular events underlying the preconditioning effects in the liver and points to the possibility of developing pharmacological approaches aimed at activating the intrinsic protective systems in patients undergoing liver surgery.展开更多
Objective: To investigate the expression of myocardium connexin 43(Cx43) in late exercise preconditioning(LEP) cardioprotection. Methods: Eight-week-old adult male Sprague Dawley rats were randomly assigned into four ...Objective: To investigate the expression of myocardium connexin 43(Cx43) in late exercise preconditioning(LEP) cardioprotection. Methods: Eight-week-old adult male Sprague Dawley rats were randomly assigned into four groups(n=8). Myocardial injury was judged in accordance with serum levels of c Tn and NT-pro BNP as well as hematoxylin basicfuchsin picric acid staining of myocardium. Cx43 m RNA was detected by in situ hybridization and qualified by real-time fluorescence quantitative PCR. Cx43 protein was localized by immunohistochemistry and its expression level was determined by western blotting. Results: The LEP obviously attenuated the myocardial ischemia/hypoxia injury caused by exhaustive exercise. There was no significant difference of Cx43 m RNA level between the four groups. Cx43 protein level was decreased significantly in group EE(P<0.05). However, LEP produced a significant increase in Cx43 protein level(P<0.05), and the decreased Cx43 protein level in exhaustive exercise was significantly up-regulated by LEP(P<0.05). Conclusions: LEP protects rat heart against exhaustive exercise-induced myocardial injury by up-regulating the expression of myocardial Cx43.展开更多
Murry et al in 1986 discovered the intrinsic mechanism of profound protection called ischemic preconditioning. The complex cellular signaling cascades underlying this phenomenon remain controversial and are only parti...Murry et al in 1986 discovered the intrinsic mechanism of profound protection called ischemic preconditioning. The complex cellular signaling cascades underlying this phenomenon remain controversial and are only partially understood. However, evidence suggests that adenosine, released during the initial ischemic insult, activates a variety of G protein-coupled agonists, such as opioids, bradykinin, and catecholamines, resulting in the activation of protein kinases, especially protein kinase C(PKC). This leads to the translocation of PKC from the cytoplasm to the sarcolemma, where it stimulates the opening of the ATP-sensitive K+ channel, which confers resistance to ischemia. It is known that a range of different hypoglycemic agents that activate the same signaling cascades at various cellular levels can interfere with protection from ischemic preconditioning. This review examines the effects of several hypoglycemic agents on myocardial ischemic preconditioning in animal studies and clinical trials.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
Liver preconditioning (PC), defined as an enhanced tolerance to injuring stimuli induced by previous specific maneuvers triggering beneficial functional and molecular changes, is of crucial importance in human liver t...Liver preconditioning (PC), defined as an enhanced tolerance to injuring stimuli induced by previous specific maneuvers triggering beneficial functional and molecular changes, is of crucial importance in human liver transplantation and major hepatic resection. For these reasons, numerous PC strategies have been evaluated in experimental models of ischemia-reperfusion liver injury, which have not been transferred to clinical application due to side effects, toxicity and difficulties in implementation, with the exception of the controversial ischemic PC. In recent years, our group has undertaken the assessment of alternate experimental liver PC protocols that might have application in the clinical setting. These include thyroid hormone (T3), n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA), or iron, which suppressed liver damage due to the 1 h ischemia-20 h reperfusion protocol. T3, n-3 LCPUFA and iron are hormetic agents that trigger biologically beneficial effects in the low-dose range, whose multifactorial mechanisms of action are discussed in the work.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
BACKGROUND Hepatectomy with inflow occlusion results in ischemia-reperfusion injury;however,pharmacological preconditioning can prevent such injury and optimize the postoperative recovery of hepatectomized patients.Th...BACKGROUND Hepatectomy with inflow occlusion results in ischemia-reperfusion injury;however,pharmacological preconditioning can prevent such injury and optimize the postoperative recovery of hepatectomized patients.The normal inflammatory response after a hepatectomy involves increased expression of metalloproteinases,which may signal pathologic hepatic tissue reformation.AIM To investigate the effect of desflurane preconditioning on these inflammatory indices in patients with inflow occlusion undergoing hepatectomy.METHODS This is a single-center,prospective,randomized controlled trial conducted at the 4th Department of Surgery of the Medical School of Aristotle University of Thessaloniki,between August 2016 and December 2017.Forty-six patients were randomized to either the desflurane treatment group for pharmacological preconditioning(by replacement of propofol with desflurane,administered 30 min before induction of ischemia)or the control group for standard intravenous propofol.The primary endpoint of expression levels of matrix metalloproteinases and their inhibitors was determined preoperatively and at 30 min posthepatic reperfusion.The secondary endpoints of neutrophil infiltration,coagulation profile,activity of antithrombin III(AT III),protein C(PC),protein S and biochemical markers of liver function were determined for 5 d postoperatively and compared between the groups.RESULTS The desflurane treatment group showed significantly increased levels of tissue inhibitor of metalloproteinases 1 and 2,significantly decreased levels of matrix metalloproteinases 2 and 9,decreased neutrophil infiltration,and less profound changes in the coagulation profile.During the 5-d postoperative period,all patients showed significantly decreased activity of AT III,PC and protein S(vs baseline values,P<0.05).The activity of AT III and PC differed significantly between the two groups from postoperative day 1 to postoperative day 5(P<0.05),showing a moderate drop in activity of AT III and PC in the desflurane treatment group and a dramatic drop in the control group.Compared to the control group,the desflurane treatment group also had significantly lower international normalized ratio values on all postoperative days(P<0.005)and lower serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase values on postoperative days 2 and 3(P<0.05).Total length of stay was significantly less in the desflurane group(P=0.009).CONCLUSION Desflurane preconditioning can lessen the inflammatory response related to ischemia-reperfusion injury and may shorten length of hospitalization.展开更多
BACKGROUND: Hypoxic preconditioning can protect hepatocytes against hypoxic injury, but its mechanism has not been elucidated. The aim of this study was to profile gene expression patterns involved in hypoxic precondi...BACKGROUND: Hypoxic preconditioning can protect hepatocytes against hypoxic injury, but its mechanism has not been elucidated. The aim of this study was to profile gene expression patterns involved in hypoxic preconditioning and probable mechanism at the level of gene expression. METHODS: Hepatocytes were divided into 2 groups: control group and hypoxic preconditioning group. Biotinlabeled cRNA from the control group and the hypoxic preconditioning group was hybridized by oligonucleotide microarray. Genes that were significantly associated with hypoxic preconditioning were filtered, and validated at the level of transcript expression. RESULTS: Forty-three genes with significantly altered expression patterns were discovered and most of them had not been previously reported. Among these genes,genes encoding superoxide dismutase 2 (SOD2)and interleukin 10 (IL-10) in the hypoxic preconditioning group were confirmed to be up-regulated with real-time quantitative PCR. CONCLUSIONS: Many cytokines are involved in hypoxic preconditioning and protect hepatocytes from hypoxiareoxygenation injury, and the increase of oxygen freeradical scavengers and anti-inflammatory factors may play a key role in this phenomenon. Diverse signal pathways are probably involved.展开更多
文摘In this editorial,we comment on the article published in the recent issue of the World Journal of Stem Cells.They focus on stem cell preconditioning to prevent ferroptosis by modulating the cystathionineγ-lyase/hydrogen sulfide(H_(2)S)pathway as a novel approach to treat vascular disorders,particularly pulmonary hypertension.Preconditioned stem cells are gaining popularity in regenerative medicine due to their unique ability to survive by resisting the harsh,unfavorable microenvironment of the injured tissue.They also secrete various paracrine factors against apoptosis,necrosis,and ferroptosis to enhance cell survival.Ferroptosis,a regulated form of cell death characterized by iron accumulation and oxidative stress,has been implicated in various pathologies encompassing dege-nerative disorders to cancer.The lipid peroxidation cascade initiates and sustains ferroptosis,generating many reactive oxygen species that attack and damage multiple cellular structures.Understanding these intertwined mechanisms provi-des significant insights into developing therapeutic modalities for ferroptosis-related diseases.This editorial primarily discusses stem cell preconditioning in modulating ferroptosis,focusing on the cystathionase gamma/H_(2)S ferroptosis pathway.Ferroptosis presents a significant challenge in mesenchymal stem cell(MSC)-based therapies;hence,the emerging role of H_(2)S/cystathionase gamma/H_(2) S signaling in abrogating ferroptosis provides a novel option for therapeutic intervention.Further research into understanding the precise mechanisms of H_(2)S-mediated cytoprotection against ferroptosis is warranted to enhance the thera-peutic potential of MSCs in clinical settings,particularly vascular disorders.
基金This study was approved by the Medical Ethics Committee of Shanxi Medical University(Approval No.2018LL016).
文摘BACKGROUND Mesenchymal stem cells(MSCs)have great potential for the treatment of various immune diseases due to their unique immunomodulatory properties.However,MSCs exposed to the harsh inflammatory environment of damaged tissue after intravenous transplantation cannot exert their biological effects,and therefore,their therapeutic efficacy is reduced.In this challenging context,an in vitro preconditioning method is necessary for the development of MSC-based therapies with increased immunomodulatory capacity and transplantation efficacy.AIM To determine whether hypoxia and inflammatory factor preconditioning increases the immunosuppressive properties of MSCs without affecting their biological characteristics.METHODS Umbilical cord MSCs(UC-MSCs)were pretreated with hypoxia(2%O_(2))exposure and inflammatory factors(interleukin-1β,tumor necrosis factor-α,interferon-γ)for 24 h.Flow cytometry,polymerase chain reaction,enzyme-linked immunosorbent assay and other experimental methods were used to evaluate the biological characteristics of pretreated UC-MSCs and to determine whether pretreatment affected the immunosuppressive ability of UC-MSCs in coculture with immune cells.RESULTS Pretreatment with hypoxia and inflammatory factors caused UC-MSCs to be elongated but did not affect their viability,proliferation or size.In addition,pretreatment significantly decreased the expression of coagulationrelated tissue factors but did not affect the expression of other surface markers.Similarly,mitochondrial function and integrity were retained.Although pretreatment promoted UC-MSC apoptosis and senescence,it increased the expression of genes and proteins related to immune regulation.Pretreatment increased peripheral blood mononuclear cell and natural killer(NK)cell proliferation rates and inhibited NK cell-induced toxicity to varying degrees.CONCLUSION In summary,hypoxia and inflammatory factor preconditioning led to higher immunosuppressive effects of MSCs without damaging their biological characteristics.
文摘AIM:To study the effects of preconditioning on inducible nitric oxide synthase(iNOS)and interleukin 1(IL-1)receptor transcription in rat liver ischemia/reperfusion injury(IRI).METHODS:Seventy-two male rats were randomized into 3 groups:the one-hour segmental ischemia(IRI,n=24)group,the ischemic preconditioning(IPC,n=24)group or the remote ischemic preconditioning(RIPC,n=24)group.The IPC and R-IPC were performed as 10 min of ischemia and 10 min of reperfusion.The iNOS and the IL-1 receptor mRNA in the liver tissue was analyzed with real time PCR.The total Nitrite and Nitrate(NOx)in continuously sampled microdialysate(MD)from the liver was analyzed.In addition,the NOx levels in the serum were analyzed.RESULTS:After 4 h of reperfusion,the iNOS mRNA was significantly higher in the R-IPC(ΔCt:3.44±0.57)group than in the IPC(ΔCt:5.86±0.82)group(P=0.025).The IL-1 receptor transcription activity was reduced in the IPC group(ΔCt:1.88±0.53 to 4.81±0.21),but not in the R-IPC group,during reperfusion(P=0.027).In the MD,a significant drop in the NOx levels was noted in the R-IPC group(12.3±2.2 to 4.7±1.2μmol/L)at the end of ischemia compared with the levels in early ischemia(P=0.008).A similar trend was observed in the IPC group(11.8±2.1 to 6.4±1.5μmol/L),although this difference was not statistically significant.The levels of NOx rose quickly during reperfusion in both groups.CONCLUSION:IPC,but not R-IPC,reduces iNOS and IL-1 receptor transcription during early reperfusion,indicating a lower inflammatory reaction.NOx is consumed in the ischemic liver lobe.
基金supported by grants from the Health Bureau(H200770)Technology Bureau(BS2005038)of Jiangsu Province,China
文摘BACKGROUND:Hepatocyte apoptosis is a severe form of cell death after hepatic ischemia-reperfusion injury(HIRI), and its relief is an important issue in liver transplantation. Hypoxic preconditioning(HP)is considered to have protective effects on HIRI.This study was designed to explore the impact of HP on apoptosis and its possible mechanism during orthotopic liver autotransplantation. METHODS:A modified orthotopic liver autotransplantation model was used to simulate HIRI.Sprague-Dawley rats were randomly divided into normal control,autotransplantation (AT)and HP groups.The HP group was subjected to an 8%oxygen atmosphere for 90 minutes before surgery.At 1,6 and 24 hours after surgery,the rats were killed and their liver tissue was sampled to assess the expression of Bcl-2 protein.The samples were subjected to blood chemistry study,morphological study under a light or transmission electron microscope,and quantitative study of mitochondria. RESULTS:The serum levels of ALT and AST in the HP group were lower than those in the AT group at 1,6 and 24 hours after orthotopic liver autotransplantation(P<0.05).Bcl-2 protein expression was increased in the HP group at each measurement point(P<0.05).Light microscopy showed that hepatic injury in the AT group was much more severe than in the HP group.Hepatocytes in the AT group showed typical apoptosis signs under a transmission electron microscope.The ultrastructural appearance of hepatocytes in the HP group was much better than in the AT group,and the area,perimeter and diameter of the mitochondria were smaller in the HP group than in the AT group(P<0.05). CONCLUSIONS:Hepatocytes sense and respond to decreased tissue oxygenation.Stimulation by HP relieves apoptosis by upregulating expression of Bcl-2 protein and its protection of mitochondria after orthotopic liver autotransplantation.
文摘BACKGROUND:Ischemia-reperfusion injury occurs when ischemic tissues or organs suffer from further functional and structural damage when their blood supply recovers.This study aimed to contrast the protective effects of ischemic preconditioning and ischemic postconditioning in hepatic ischemia-reperfusion injury in rats.METHODS:Thirty-two healthy male Wistar rats were randomly divided into four groups:sham-operated(SO),ischemia-reperfusion(IR),ischemic preconditioning(I-pre),and ischemic postconditioning(I-post).Blood samples and hepatic tissue were taken from all groups after the experiments.RESULTS:There were significant differences between the IR,I-pre and I-post groups in alanine aminotransferase and aspartate aminotransferase levels,NF-κB p65 expression,apoptosis index and superoxide dismutase activity in hepatic tissue.There were no significant differences between the I-pre and I-post groups.CONCLUSIONS:Ischemic postconditioning and ischemic preconditioning reduce hepatic ischemia-reperfusion injury,but in clinical practice the former is a more appropriate choice.
基金Supported by The Deutsche Forschungsgemeinschaft, No. DFG SCHA 857/1-1
文摘AIM:To characterize the impact of the Pringle ma-neuver (PM) and ischemic preconditioning (IP) on total blood supply to the liver following hepatectomies. METHODS: Sixty one consecutive patients who un-derwent hepatic resection under in flow occlusion were randomized either to receive PM alone (n = 31) or IP (10 min of ischemia followed by 10 min of reperfusion) prior to PM (n = 30). Quantification of liver perfusion was measured by Doppler probes at the hepatic artery and portal vein at various time points after reperfusion of remnant livers. RESULTS: Occlusion times of 33 ± 12 min (mean ± SD) and 34 ± 14 min and the extent of resected liver tissue (2.7 segments) were similar in both groups. In controls (PM), on reperfusion of liver remnants for 15 min, portal perfusion markedly decreased by 29% while there was a slight increase of 8% in the arterial blood flow. In contrast, following IP + PM the portal vein flow remained unchanged during reperfusion and a significantly increased arterial blood flow (+56% vs baseline) was observed. In accordance with a better postischemic blood supply of the liver, hepatocellular injury, as measured by alanine aminotransferase (ALT) levels on day 1 was considerably lower in group B compared to group A (247 ± 210 U/I vs 550 ± 650 U/I, P < 0.05). Additionally, ALT levels were significantly correlated to the hepatic artery in flow.CONCLUSION: IP prevents postischemic flow reduction of the portal vein and simultaneously increases arterial perfusion, suggesting that improved hepatic macrocirculation is a protective mechanism following hepatectomy.
文摘BACKGROUND: Ischemia/reperfusion is the main cause of hepatic damage in liver transplantation. Immediate early genes (IEGs) encode proteins can regulate expression of cellular response genes after injury, and is associated with tissue repair and cell apoptosis. The purpose of this re- search was to investigate the effects of preconditioning on expression of immediate early genes c-fos and c-jun follow- ing hepatic ischemia/reperfusion (IR) and its roles in cellu- lar regeneration and apoptosis. METHODS: Ninety-six Wistar rats were randomly divided into IR group and hepatic ischemic preconditioning (IPC) group, and each group was further divided into eight sub- groups (n =6). The model of partial liver ischemia/reper- fusion was used. The rats were subjected to 60-minute liver ischemia, preceded by 10-minute preconditioning. After 0-, 0.5-, 1-, 2-, 4-, 8-, 12-, 24-hour reperfusion, the se- rum and liver tissue in each group were collected to detect the level of serum ALT/AST, liver histopathology, expres- sion of c-fos, and c-jun mRNA. Flow cytometer was used to detect Ki67 and Sub-G1 as the quantity indicators of cell regeneration and apoptosis respectively. RESULTS: Compared with IR group, IPC group showed a significantly lower ALT/AST level in 0. 5-hour sub-group to 8-hour sub-group (P<0.05). Ki67 elevated significantly at 0.5, 1, 2 hours, but decreased significantly at 24 hours ( P < 0 . 05). Ap index decreased significantly after 1-hour reperfusion(P<0.05). Expressions of c-fos and c-jun mR- NA were low, especially c-jun at 0.5, 1 and 2 hours after reperfusion. CONCLUSION: Ischemic preconditioning can protect liver cells against ischemia/reperfusion injury, and this protec- tive effect may be related to influence transcription levels of c-fos and c-jun.
基金supported by grants from the National Key Technology R&D Program in the Eleventh Five-Year Plan of China (No. 2008BAI60B02 and 2008BAI60B06)the National Natural Science Foundation of China (No. 30700769)
文摘BACKGROUND: Liver transplantation is so far the most effective therapeutic modality for end-stage liver diseases, but ischemia/reperfusion (I/R) injury represents a critical barrier to liver transplantation. Primary graft dysfunction and small-for-size syndrome are closely associated with I/R injury. Ischemic preconditioning (IPC) is defined as a brief period of liver ischemia followed by reperfusion, and has demonstrated protections against a prolonged I/R injury and improved the capacity of regeneration. The article aimed to review IPC literatures for the understanding of the effects of IPC on I/R injury involving in the procurement of donor liver and protective mechanisms. DATA SOURCES: A literature search of MEDLINE and Web of Science databases using "liver transplantation", "liver regeneration", "hepatectomy", "ischemia/reperfusion" and "ischemic preconditioning" was performed, and then a large amount of related data was collected. RESULTS: The literature search provided a huge amount of evidence for the protective effects of IPC on I/R injury in liver transplantation, including reduction of blood loss in hepatectomy, intraoperative hemodynamic stability and its significant role in liver regeneration. The mechanism involves in balancing inflammatory cytokines, enhancing energy status and mitigating microcirculatory disturbance.CONCLUSION: IPC plays an essential role in hepatectomy before and after harvest of living donor liver and implantation of liver graft.
基金supported by National Natural Science Foundation of China,No.81771270(to QP)Inner Mongolia Science Foundation of China,No.2020MS08063(to YQP)+3 种基金Health and Family Planning Scientific Research Plan Project of Inner Mongolia Autonomous Region of China,No.201702138(to YQP)Baotou Science and Technology Plan Project of China,No.2018C2007-4-10(to YQP)Baotou Medical and Health Science and Technology Project of China,No.wsjj2019036(to JY)Baotou Medical College Foundation of China,No.BSJJ201904(to JY)。
文摘Hypoxic preconditioning can protect against cerebral ischemia/reperfusion injury. However, the underlying mechanisms that mediate this effect are not completely clear. In this study, mice were pretreated with continuous, intermittent hypoxic preconditioning;1 hour later, cerebral ischemia/reperfusion models were generated by middle cerebral artery occlusion and reperfusion. Compared with control mice, mice with cerebral ischemia/reperfusion injury showed increased Bederson neurological function scores, significantly increased cerebral infarction volume, obvious pathological damage to the hippocampus, significantly increased apoptosis;upregulated interleukin-1β, interleukin-6, and interleukin-8 levels in brain tissue;and increased expression levels of NOD-like receptor family pyrin domain containing 3(NLRP3), NLRP inflammasome-related protein caspase-1, and gasdermin D. However, hypoxic preconditioning significantly inhibited the above phenomena. Taken together, these data suggest that hypoxic preconditioning mitigates cerebral ischemia/reperfusion injury in mice by reducing NLRP3 inflammasome expression. This study was approved by the Medical Ethics Committee of the Fourth Hospital of Baotou, China(approval No. DWLL2019001) in November 2019.
基金Supported by Grants from the Fundamental Research Funds for the Central Universities,No.2013JDHZ08Personnel training Specialized Research Fundation of The Second Affiliated Hospital of Xi’an Jiaotong University of China,No.RC(GG)201404
文摘AIM: To evaluate preventative effects of ischemic preconditioning(IP) in a rat model of intestinal injury induced by ischemia-reperfusion(IR).METHODS: Male Sprague-Dawley rats(250-300 g) were fasted for 24 h with free access to water prior to the operation.Eighteen rats were randomly divided into three experimental groups: S group(n = 6),rats were subjected to isolation of the superior mesenteric artery(SMA) for 40 min,then the abdomen was closed; IRgroup(n = 6),rats were subjected to clamping the SMA 40 min,and the abdomen was closed followed by a 4-h reperfusion; IP group(n = 6) rats underwent three cycles of 5 min ischemia and 5 min reperfusion,then clamping of the SMA for 40 min,then the abdomen was closed and a 4-h reperfusion followed.All animals were euthanized by barbiturate overdose(150 mg/kg pentobarbital sodium,i.v.) for tissue collection,and the SMA was isolated via median abdominal incision.Intestinal histologic injury was observed.Malondialdehyde(MDA),myeloperoxidase(MPO) and tumor necrosis factor(TNF)-a concentrations in intestinal tissue were measured.Intercellular adhesion molecule(ICAM)-1 and vascular cell adhesion molecule(VCAM)-1 expression,as well as nuclear factor(NF)-κB activity and expression in intestinal tissue were also determined.RESULTS: Compared with the IR group,IP reduced IR-induced histologic injury of the intestine in rats(2.00 ± 0.71 vs 3.60 ± 0.84,P < 0.05).IP significantly inhibited the increase in MDA content(5.6 ± 0.15 μmol/L vs 6.84 ± 0.18 μmol/L,P < 0.01),MPO activity(0.13 ± 0.01 U/L vs 0.24 ± 0.01 U/L,P < 0.01),and TNF-a levels(7.79 ± 2.35 pg/m L vs 10.87 ± 2.48 pg/m L,P < 0.05) in the intestinal tissue of rats.IP also markedly ameliorated the increase in ICAM-1(204.67 ± 53.27 vs 353.33 ± 45.19,P < 0.05) and VCAM-1(256.67 ± 58.59 vs 377.33 ± 41.42,P < 0.05) protein expression in the intestinal tissues.Additionally,IP remarkably decreased NF-κB activity(0.48 ± 0.16 vs 0.76 ± 0.22,P < 0.05) and protein expression(320.23 ± 38.16 vs 520.76 ± 40.53,P < 0.01) in rat intestinal tissue.CONCLUSION: IP may protect against IR-induced intestinal injury by attenuation of the neutrophilendothelial adhesion cascade via reducing ICAM-1 and VCAM-1 expression and TNF-a-induced NF-κB signaling pathway activity.
基金supported by a grant from Sāo Paulo Foundation Research FAPESP 2011/05214-3
文摘BACKGROUND: Ischemic preconditioning(IPC) has been shown to decrease liver injury and to increase hepatic microvascular perfusion after liver ischemia reperfusion. This study aimed to evaluate the effects of IPC on hemodynamics of the portal venous system. METHODS: Thirty-two rats were randomized into two groups: IPC group and control group. The rats of the IPC group underwent IPC by 10 minutes of liver ischemia followed by 10 minutes of reperfusion before liver ischemia, and the rats of the control group were subjected to 60 minutes of partial liver ischemia. Non-ischemic lobes were resected immediately after reperfusion. The animals were studied at 4 hours and 12 hours after reperfusion. Mean arterial pressure, heart rate, portal vein flow and pressure were analyzed. Blood was collected for the determination of the levels of aspartate aminotransferase, alanine aminotransferase, calcium, lactate, pH, bicarbonate, and base excess. RESULTS: IPC increased the mean portal vein flow at 4 hours and 12 hours after reperfusion. IPC recovered 78% of the meanportal vein flow at 12 hours after reperfusion. IPC decreased the levels of aspartate aminotransferase, alanine aminotransferase and lactate, and increased the levels of ionized calcium, bicarbonate and base excess at 12 hours after reperfusion. CONCLUSIONS: This study demonstrated that IPC increases portal vein flow and enhances hepatoprotective effects in liver ischemia reperfusion. The better recovery of portal vein flow after IPC may be correlated with the lower levels of transaminases and with the better metabolic profile.
文摘AIM:To investigate the effect of repeated lower +Gzexposure on liver injury induced by high +Gz exposure in rats.METHODS:Sixty male Wister rats were randomly divided into a blank control group,a low G preconditioning group(LG)(exposed to +4 Gz/5 min per day for 3 d before +10 Gz/5 min exposure),and a +10 Gz/5 min group(10G)(n = 20 in each group).Blood specimens and liver tissue were harvested at 0 h and 6 h after +10 Gz/5 min exposure.Liver function was analyzed by measuring serum alanine transaminase(ALT) and aspartate aminotransferase(AST) levels,and liver injury was further assessed by histopathological observation.Malondialdehyde(MDA),superoxide dismutase(SOD) and Na+-K+-ATPase were determined in hepatic tissue.RESULTS:The group LG had lower ALT,AST,and MDA values at 0 h after exposure than those in group 10 G.SOD values and Na+-K+-ATPase activity in the LG group were higher than in group 10 G 0 h post-exposure.Hepatocyte injury was significantly less in group LG than in group 10 G on histopathological evaluation.CONCLUSION:It is suggested that repeated low +Gz exposure shows a protective effect on liver injury induced by high +Gz exposure in rats.
基金Supported by The Regional Government of Piedmont, Italy (Carini, Fondi Ricerca Sanitaria Finalizzata, 2006, 2007 2008, 2008 bis, 2009+1 种基金 Alchera, Fondi Ricerca Sanitaria Finalizzata, 2008 bis, 2009)the University "Amedeo Avogadro"
文摘Ischemia/reperfusion (I/R) injury still represents an important cause of morbidity following hepatic surgery and limits the use of marginal livers in hepatic transplantation. Transient blood flow interruption followed by reperfusion protects tissues against damage induced by subsequent I/R. This process known as ischemic pre-conditioning (IP) depends upon intrinsic cytoprotective systems whose activation can inhibit the progression of irreversible tissue damage. Compared to other organs,liver IP has additional features as it reduces inflammation and promotes hepatic regeneration. Our present understanding of the molecular mechanisms involved in liver IP is still largely incomplete. Experimental studies have shown that the protective effects of liver IP are triggered by the release of adenosine and nitric oxide and the subsequent activation of signal networks involving protein kinases such as phosphatidylinositol 3-kinase,protein kinase C δ/ε and p38 MAP kinase,and transcription factors such as signal transducer and activator of transcription 3,nuclear factor-κB and hypoxia-inducible factor 1. This article offers an overview of the molecular events underlying the preconditioning effects in the liver and points to the possibility of developing pharmacological approaches aimed at activating the intrinsic protective systems in patients undergoing liver surgery.
基金supported by Chinese Postdoctoral Science Foundation(No.2014N560538)Hainan Province Colleges and Universities Scientific Research Project(No.Hnky2015-34)Project of Natural Science Foundation of Hainan Province(314090)
文摘Objective: To investigate the expression of myocardium connexin 43(Cx43) in late exercise preconditioning(LEP) cardioprotection. Methods: Eight-week-old adult male Sprague Dawley rats were randomly assigned into four groups(n=8). Myocardial injury was judged in accordance with serum levels of c Tn and NT-pro BNP as well as hematoxylin basicfuchsin picric acid staining of myocardium. Cx43 m RNA was detected by in situ hybridization and qualified by real-time fluorescence quantitative PCR. Cx43 protein was localized by immunohistochemistry and its expression level was determined by western blotting. Results: The LEP obviously attenuated the myocardial ischemia/hypoxia injury caused by exhaustive exercise. There was no significant difference of Cx43 m RNA level between the four groups. Cx43 protein level was decreased significantly in group EE(P<0.05). However, LEP produced a significant increase in Cx43 protein level(P<0.05), and the decreased Cx43 protein level in exhaustive exercise was significantly up-regulated by LEP(P<0.05). Conclusions: LEP protects rat heart against exhaustive exercise-induced myocardial injury by up-regulating the expression of myocardial Cx43.
文摘Murry et al in 1986 discovered the intrinsic mechanism of profound protection called ischemic preconditioning. The complex cellular signaling cascades underlying this phenomenon remain controversial and are only partially understood. However, evidence suggests that adenosine, released during the initial ischemic insult, activates a variety of G protein-coupled agonists, such as opioids, bradykinin, and catecholamines, resulting in the activation of protein kinases, especially protein kinase C(PKC). This leads to the translocation of PKC from the cytoplasm to the sarcolemma, where it stimulates the opening of the ATP-sensitive K+ channel, which confers resistance to ischemia. It is known that a range of different hypoglycemic agents that activate the same signaling cascades at various cellular levels can interfere with protection from ischemic preconditioning. This review examines the effects of several hypoglycemic agents on myocardial ischemic preconditioning in animal studies and clinical trials.
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.
基金Supported by Grants No. 1110006 to Fernández V to No. 1110043 to Tapia GNo. 1090020 to Videla LA from FONDECYT, Chile
文摘Liver preconditioning (PC), defined as an enhanced tolerance to injuring stimuli induced by previous specific maneuvers triggering beneficial functional and molecular changes, is of crucial importance in human liver transplantation and major hepatic resection. For these reasons, numerous PC strategies have been evaluated in experimental models of ischemia-reperfusion liver injury, which have not been transferred to clinical application due to side effects, toxicity and difficulties in implementation, with the exception of the controversial ischemic PC. In recent years, our group has undertaken the assessment of alternate experimental liver PC protocols that might have application in the clinical setting. These include thyroid hormone (T3), n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA), or iron, which suppressed liver damage due to the 1 h ischemia-20 h reperfusion protocol. T3, n-3 LCPUFA and iron are hormetic agents that trigger biologically beneficial effects in the low-dose range, whose multifactorial mechanisms of action are discussed in the work.
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.
文摘BACKGROUND Hepatectomy with inflow occlusion results in ischemia-reperfusion injury;however,pharmacological preconditioning can prevent such injury and optimize the postoperative recovery of hepatectomized patients.The normal inflammatory response after a hepatectomy involves increased expression of metalloproteinases,which may signal pathologic hepatic tissue reformation.AIM To investigate the effect of desflurane preconditioning on these inflammatory indices in patients with inflow occlusion undergoing hepatectomy.METHODS This is a single-center,prospective,randomized controlled trial conducted at the 4th Department of Surgery of the Medical School of Aristotle University of Thessaloniki,between August 2016 and December 2017.Forty-six patients were randomized to either the desflurane treatment group for pharmacological preconditioning(by replacement of propofol with desflurane,administered 30 min before induction of ischemia)or the control group for standard intravenous propofol.The primary endpoint of expression levels of matrix metalloproteinases and their inhibitors was determined preoperatively and at 30 min posthepatic reperfusion.The secondary endpoints of neutrophil infiltration,coagulation profile,activity of antithrombin III(AT III),protein C(PC),protein S and biochemical markers of liver function were determined for 5 d postoperatively and compared between the groups.RESULTS The desflurane treatment group showed significantly increased levels of tissue inhibitor of metalloproteinases 1 and 2,significantly decreased levels of matrix metalloproteinases 2 and 9,decreased neutrophil infiltration,and less profound changes in the coagulation profile.During the 5-d postoperative period,all patients showed significantly decreased activity of AT III,PC and protein S(vs baseline values,P<0.05).The activity of AT III and PC differed significantly between the two groups from postoperative day 1 to postoperative day 5(P<0.05),showing a moderate drop in activity of AT III and PC in the desflurane treatment group and a dramatic drop in the control group.Compared to the control group,the desflurane treatment group also had significantly lower international normalized ratio values on all postoperative days(P<0.005)and lower serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase values on postoperative days 2 and 3(P<0.05).Total length of stay was significantly less in the desflurane group(P=0.009).CONCLUSION Desflurane preconditioning can lessen the inflammatory response related to ischemia-reperfusion injury and may shorten length of hospitalization.
基金This study was supported by a grant from Shanghai Technology and Science Commission Foundation (No. 024107010).
文摘BACKGROUND: Hypoxic preconditioning can protect hepatocytes against hypoxic injury, but its mechanism has not been elucidated. The aim of this study was to profile gene expression patterns involved in hypoxic preconditioning and probable mechanism at the level of gene expression. METHODS: Hepatocytes were divided into 2 groups: control group and hypoxic preconditioning group. Biotinlabeled cRNA from the control group and the hypoxic preconditioning group was hybridized by oligonucleotide microarray. Genes that were significantly associated with hypoxic preconditioning were filtered, and validated at the level of transcript expression. RESULTS: Forty-three genes with significantly altered expression patterns were discovered and most of them had not been previously reported. Among these genes,genes encoding superoxide dismutase 2 (SOD2)and interleukin 10 (IL-10) in the hypoxic preconditioning group were confirmed to be up-regulated with real-time quantitative PCR. CONCLUSIONS: Many cytokines are involved in hypoxic preconditioning and protect hepatocytes from hypoxiareoxygenation injury, and the increase of oxygen freeradical scavengers and anti-inflammatory factors may play a key role in this phenomenon. Diverse signal pathways are probably involved.
