Search

OBJECTIVES Pharmacological postconditioning can protect against myocardial ischaemia-reperfusion injury during cardiac surgery with extracorporeal circulation. The aim of this study was to observe the protective effects of fructose-1,6-bisphosphate (FDP) postconditioning on myocardial ischaemia-reperfusion injury in patients undergoing cardiac valve replacement with extracorporeal circulation. METHODS Patients undergoing elective mitral valve replacement and/or aortic valve replacement were divided into normal saline postconditioning group (NS group) and FDP postconditioning group (FDP group). The primary outcome was the plasma concentration of creatine kinase-MB (CK-MB). The secondary outcomes were the plasma concentrations of lactate dehydrogenase, CK, high-sensitivity C-reactive protein, alpha-hydroxybutyrate dehydrogenase and cardiac troponin I, the spontaneous cardiac rhythm recovery profile, the extracorporeal circulation time and duration of surgery, intensive care unit and postoperative hospitalization. RESULTS Forty patients were randomly assigned to receive intervention and included in the analysis. The serum concentrations of CK-MB, lactate dehydrogenase, CK, cardiac troponin I, alpha-hydroxybutyrate dehydrogenase and high-sensitivity C-reactive protein at T1∼4 were lower in the FDP group than in the NS group (P  <   0.001). Compared with the NS group, the dosage of dopamine administered 1–90 min after cardiac resuscitation, the spontaneous cardiac rhythm recovery time and the incidence of ventricular fibrillation were lower in the FDP group (P  <   0.001, P  <   0.001 and P  =   0.040, respectively). The values of ST- changes were increased more significantly in the NS group than in the FDP group (median [standard deviation] 1.3 [0.3] mm vs 0.7 [0.2] mm; P  <   0.001). Compared with the NS group, the time of recovery of ST-segment deviations was shorter in the FDP group (50.3 [12.3] min vs 34.6 [6.9] min; P  <   0.001). CONCLUSIONS The FDP postconditioning could improve both myocardial ischaemia-reperfusion injury and the spontaneous cardiac rhythm recovery during cardiac valve surgery with extracorporeal circulation. [ABSTRACT FROM AUTHOR]

The cardioprotective effect of ischemic preconditioning (IPC) and ischemic postconditioning (IPoC) in adult hearts is mediated by nitric oxide (NO). During the early developmental period, rat hearts exhibit higher resistance to ischemia–reperfusion (I/R) injury, contain higher levels of serum nitrates, and their resistance cannot be further increased by IPC or IPoC. NOS blocker (L‐NAME) lowers their high resistance. Wistar rat hearts (postnatal Days 1 and 10) were perfused according to Langendorff and exposed to 40 min of global ischemia followed by reperfusion with or without IPoC. NO and reactive oxygen species donors (DEA‐NONO, SIN‐1) and L‐NAME were administered. Tolerance to ischemia decreased between Days 1 and 10. DEA‐NONO (low concentrations) significantly increased tolerance to I/R injury on both Days 1 and 10. SIN‐1 increased tolerance to I/R injury on Day 10, but not on Day 1. L‐NAME significantly reduced resistance to I/R injury on Day 1, but actually increased resistance to I/R injury on Day 10. Cardioprotection by IPoC on Day 10 was not affected by either NO donors or L‐NAME. It can be concluded that resistance of the neonatal heart to I/R injury is NO dependent, but unlike in adult hearts, cardioprotective interventions, such as IPoC, are most likely NO independent. [ABSTRACT FROM AUTHOR]

Abstract Background Ischemic postconditioning (IPostC) has been reported as a promising method for protecting against myocardial ischemia-reperfusion (MI/R) injury. Our previous study found that the infarct-limiting effect of IPostC is abolished in the heart of diabetes whose cardiac expression of DJ-1 (also called PARK7, Parkinsonism associated deglycase) is reduced. However, the role and in particular the underlying mechanism of DJ-1 in the loss of sensitivity to IPostC-induced cardioprotection in diabetic hearts remains unclear. Methods Streptozotocin-induced type 1 diabetic rats were subjected to MI/R injury by occluding the left anterior descending artery (LAD) and followed by reperfusion. IPostC was induced by three cycles of 10s of reperfusion and ischemia at the onset of reperfusion. AAV9-CMV-DJ-1, AAV9-CMV-C106S-DJ-1 or AAV9-DJ-1 siRNA were injected via tail vein to either over-express or knock-down DJ-1 three weeks before inducing MI/R. Results Diabetic rats subjected to MI/R exhibited larger infarct area, more severe oxidative injury concomitant with significantly reduced cardiac DJ-1 expression and increased PTEN expression as compared to non-diabetic rats. AAV9-mediated cardiac DJ-1 overexpression, but not the cardiac overexpression of DJ-1 mutant C106S, restored IPostC-induced cardioprotection and this effect was accompanied by increased cytoplasmic DJ-1 translocation toward nuclear and mitochondrial, reduced PTEN expression, and increased Nrf-2/HO-1 transcription. Our further study showed that AAV9-mediated targeted DJ-1 gene knockdown aggravated MI/R injury in diabetic hearts, and this exacerbation of MI/R injury was partially reversed by IPostC in the presence of PTEN inhibition or Nrf-2 activation. Conclusions These findings suggest that DJ-1 preserves the cardioprotective effect of IPostC against MI/R injury in diabetic rats through nuclear and mitochondrial DJ-1 translocation and that inhibition of cardiac PTEN and activation of Nrf-2/HO-1 may represent the major downstream mechanisms whereby DJ-1 preserves the cardioprotective effect of IPostC in diabetes. Graphical abstract

Background: Ischemic post-conditioning (IPoC) has been shown to improve outcomes in limited pre-clinical models. As down-time is often unknown, this technique needs to be investigated over a range of scenarios. As this tool limits reperfusion injury, there may be limited benefit or even harm after short arrest and limited ischemia-reperfusion injury. Methods: Eighteen male Wistar rats underwent 7 min of asphyxial arrest. Animals randomized to IPoC received a 20 s pause followed by 20 s of compressions, repeated four times, initiated 40 s into cardiopulmonary resuscitation. If return of spontaneous circulation (ROSC) was achieved, epinephrine was titrated to mean arterial pressure (MAP) of 70 mmHg. Data were analyzed using t-test or Mann–Whitney test. Significance set at p ≤ 0.05. Results: The rate of ROSC was equivalent in both groups, 88%. There was no statistically significant difference in time to ROSC, epinephrine required post ROSC, carotid flow, or peak lactate at any timepoint. There was a significantly elevated MAP with IPoC, 90.7 mmHg (SD 13.9), as compared to standard CPR, 76.7 mmHg (8.5), 2 h after ROSC, p = 0.03. Conclusions: IPoC demonstrated no harm in a model of short arrest using a new arrest etiology for CPR based IPoC intervention in a rat model. [ABSTRACT FROM AUTHOR]

Objective: Acute ischemic stroke (AIS) is a significant health burden in China, affecting a sizable portion of the population. Conventional pharmacological treatments frequently fall short of desirable outcomes. Therefore, exploring alternative therapies is crucial. Remote ischemic postconditioning (RIPostC) is a noninvasive and cost-effective adjunctive therapy. This study aimed to investigate the efficacy and safety of RIPostC as an adjunctive therapy for AIS to inform clinical practice. Methods: A comprehensive search was conducted across the PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), WanFang, Weipu (VIP), and China Biology Medicine disc (CBM) databases up to October 2023. All included studies underwent bias risk assessment using the Cochrane risk-of-bias assessment tool. The primary outcome measure was the National Institute of Health Stroke Scale (NIHSS), with secondary outcomes including the Barthel index (BI), D-dimer, C-reactive protein (CRP), fibrinogen (FIB), brain-derived neurotrophic factor (BDNF), modified Rankin scale (mRS), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) levels. The data were analyzed using fixed-effects and random-effects models in Review Manager, with mean differences (MDs) and 95% confidence intervals (CIs) calculated for each outcome. The grading of recommendations, assessment, development, and evaluations (GRADE) approach was used to evaluate the level of evidence for each outcome measure. Results: This meta-analysis included 38 studies, encompassing 4334 patients. Compared with the control group, the RIPostC group had significantly lower NIHSS scores, serum CRP, D-dimer, IL-6, TNF-α, and FIB levels, and increased BDNF levels. Moreover, it improved the patient's BI and mRS scores. According to the GRADE approach, the quality of evidence for mRS was deemed "moderate," while the NIHSS, BI, and CRP were rated as "low" quality. IL-6, TNF-α, FIB, D-dimer, and BDNF received "very low" quality ratings. Conclusion: The findings suggest that RIPostC activates endogenous protective mechanisms, providing benefits to patients with AIS. [ABSTRACT FROM AUTHOR]

BACKGROUND: Ischemic postconditioning is one of the effective ways to reduce ischemia-reperfusion injury and has been more and more widely used in clinical practice in recent years, but its specific molecular mechanism has yet to be studied. OBJECTIVE: To investigate the role and mechanism of piRNA-005854 in the aging cardiomyocytes caused by hypoxic postconditioning. METHODS: In vitro, cardiomyocytes were administered 8 mg/mL D-galactose for 9 days to induce their aging. β-Galactosidase staining was used to observe the aging of cardiomyocytes. Senescent cells were treated with hypoxia/reoxygenation and hypoxic postconditioning. ELISA was utilized to detect changes in myocardial injury markers creatine kinase isoenzyme MB and lactate dehydrogenase levels. Western blot assay was applied to detect the expression changes of autophagy-related proteins LC3II, p62, ULK1 and phosphorylated ULK1 in aging cardiomyocytes. qRT-PCR was employed to determine the expression level of piRNA-005854. piRNA-005854 inhibitor and piRNA-005854 mimics were transferred into aging cardiomyocytes and followed with hypoxic postconditioning. Western blot assay was used to examine the expression of LC3II, p62, ULK1 and phosphorylated ULK1. RESULTS AND CONCLUSION: (1) D-galactose induced obvious senescence of cardiomyocytes 9 days later. (2) Compared with the normoxia group, creatine kinase isoenzyme MB and lactate dehydrogenase levels increased in the hypoxia/reoxygenation group (P < 0.01); LC3 II/I expression was increased; p62 expression was decreased; ULK1 phosphorylation level was increased, and piRNA-005854 expression was increased (P < 0.01). (3) Compared with the hypoxia/ reoxygenation group, creatine kinase isoenzyme MB and lactate dehydrogenase levels significantly reduced in the hypoxic postconditioning group (P < 0.01); LC3 II/I expression significantly decreased (P < 0.05); p62 expression increased (P < 0.01); ULK1 phosphorylation level decreased (P < 0.05), and piRNA-005854 expression decreased (P < 0.01). (4) After transfection of piRNA-005854 inhibitor, LC3II/I expression was decreased (P < 0.01); the expression of p62 was increased significantly (P < 0.05); the phosphorylation level of ULK1 was decreased significantly (P < 0.01). After transfection of piRNA-005854 mimics, LC3II/ I expression was increased significantly; the expression of p62 was decreased, and the phosphorylation level of ULK1 was increased significantly (P < 0.01). (5) The results show that piRNA-005854-mediated reduction of ULK1-dependent autophagy level is a possible mechanism that hypoxic postconditioning exerts its protective effect on aging cardiomyocytes. [ABSTRACT FROM AUTHOR]

Background: Ischemic postconditioning (IPostC) has been reported as a promising method for protecting against myocardial ischemia-reperfusion (MI/R) injury. Our previous study found that the infarct-limiting effect of IPostC is abolished in the heart of diabetes whose cardiac expression of DJ-1 (also called PARK7, Parkinsonism associated deglycase) is reduced. However, the role and in particular the underlying mechanism of DJ-1 in the loss of sensitivity to IPostC-induced cardioprotection in diabetic hearts remains unclear. Methods: Streptozotocin-induced type 1 diabetic rats were subjected to MI/R injury by occluding the left anterior descending artery (LAD) and followed by reperfusion. IPostC was induced by three cycles of 10s of reperfusion and ischemia at the onset of reperfusion. AAV9-CMV-DJ-1, AAV9-CMV-C106S-DJ-1 or AAV9-DJ-1 siRNA were injected via tail vein to either over-express or knock-down DJ-1 three weeks before inducing MI/R. Results: Diabetic rats subjected to MI/R exhibited larger infarct area, more severe oxidative injury concomitant with significantly reduced cardiac DJ-1 expression and increased PTEN expression as compared to non-diabetic rats. AAV9-mediated cardiac DJ-1 overexpression, but not the cardiac overexpression of DJ-1 mutant C106S, restored IPostC-induced cardioprotection and this effect was accompanied by increased cytoplasmic DJ-1 translocation toward nuclear and mitochondrial, reduced PTEN expression, and increased Nrf-2/HO-1 transcription. Our further study showed that AAV9-mediated targeted DJ-1 gene knockdown aggravated MI/R injury in diabetic hearts, and this exacerbation of MI/R injury was partially reversed by IPostC in the presence of PTEN inhibition or Nrf-2 activation. Conclusions: These findings suggest that DJ-1 preserves the cardioprotective effect of IPostC against MI/R injury in diabetic rats through nuclear and mitochondrial DJ-1 translocation and that inhibition of cardiac PTEN and activation of Nrf-2/HO-1 may represent the major downstream mechanisms whereby DJ-1 preserves the cardioprotective effect of IPostC in diabetes. [ABSTRACT FROM AUTHOR]

Background: In recent years, stroke and ischemia--reperfusion injury has motivated researchers to find new ways to reduce the complications. Although reperfusion is essential for brain survival, it is like a double-edged sword that may cause further damage to the brain. Ischemic postconditioning (IPostC) refers to the control of blood flow in postischemia--reperfusion that can reduce ischemia-reperfusion injuries. Materials and Methods: Articles were collected by searching for the terms: Ischemic postconditioning and neuroprotective and ischemic postconditioning and hyperperfusion. Suitable articles were collected from electronic databases, including ISI Web of Knowledge, Medline/PubMed, ScienceDirect, Embase, Scopus, Biological Abstract, Chemical Abstract, and Google Scholar. Results: New investigations show that IPostC has protection against hyperperfusion by reducing the amount of blood flow during reperfusion and thus reducing infarction volume, preventing the blood--brain barrier damage, and reducing the rate of apoptosis through the activation of innate protective systems. Numerous mechanisms have been suggested for IPostC, which include reduction of free radical production, apoptosis, inflammatory factors, and activation of endogenous protective pathways. Conclusion: It seems that postconditioning can prevent damage to the brain by reducing the flow and blood pressure caused by hyperperfusion. It can protect the brain against damages such as stroke and hyperperfusion by activating various endogenous protection systems. In the present review article, we tried to evaluate both useful aspects of IPostC, neuroprotective effects, and fight against hyperperfusion. [ABSTRACT FROM AUTHOR]

Abstract The cardioprotective effect of ischemic preconditioning (IPC) and ischemic postconditioning (IPoC) in adult hearts is mediated by nitric oxide (NO). During the early developmental period, rat hearts exhibit higher resistance to ischemia–reperfusion (I/R) injury, contain higher levels of serum nitrates, and their resistance cannot be further increased by IPC or IPoC. NOS blocker (L‐NAME) lowers their high resistance. Wistar rat hearts (postnatal Days 1 and 10) were perfused according to Langendorff and exposed to 40 min of global ischemia followed by reperfusion with or without IPoC. NO and reactive oxygen species donors (DEA‐NONO, SIN‐1) and L‐NAME were administered. Tolerance to ischemia decreased between Days 1 and 10. DEA‐NONO (low concentrations) significantly increased tolerance to I/R injury on both Days 1 and 10. SIN‐1 increased tolerance to I/R injury on Day 10, but not on Day 1. L‐NAME significantly reduced resistance to I/R injury on Day 1, but actually increased resistance to I/R injury on Day 10. Cardioprotection by IPoC on Day 10 was not affected by either NO donors or L‐NAME. It can be concluded that resistance of the neonatal heart to I/R injury is NO dependent, but unlike in adult hearts, cardioprotective interventions, such as IPoC, are most likely NO independent.

Objective To investigate the protective effect of sevoflurane postconditioning against cerebral ischemia/reperfusion (I/R) injury in rats and its mechanism of action. Methods A total of 80 specific pathogen-free healthy adult male Sprague-Dawley rats were selected and randomly divided into sham-operation group (S group), cerebral I/R group (I/R group), cerebral I/R+sevoflurane postconditioning group (ISP group), and cerebral I/R+sevoflurane postconditioning+nuclear factor ery-throid 2-related factor 2 (Nrf2) inhibitor group (ISPB group), with 20 rats in each group. All rats except those in the S group were used to establish a rat model of cerebral I/R injury using the suture method for occlusion of the middle cerebral artery for 2 h, followed by reperfusion for 24 h, and for the rats in the S group, threading was performed below the middle cerebral artery without ligation. The rats in the ISP group were given inhalation of 3% sevoflurane immediately after reperfusion for 30 min, and those in the ISPB group were given intraperitoneal injection of the Nrf2 inhibitor brusatol (2 mg/kg) at 30 min before ischemia in addition to the treatment in the ISP group. After successful modeling, neurological deficit score was used to eval-uate the degree of neurological impairment. Left ventricular blood samples and pathological sections of brain tissue were obtained, and 2,3,5-triphenyltetrazolium chloride staining was used to determine the percentage of cerebral infarct volume; enzyme-linked immunosorbent assay was used to measure the serum levels of inflammatory factors (interleukin-1β [IL-1β] and tumor necrosis factor-α [TNF-α]) and oxidative stress-related factors (malondialdehyde [MDA] and superoxide dismutase [SOD]); Western blotting was used to mea-sure the expression of apoptosis-related proteins (B-cell lymphoma-2 [Bcl-2], Bcl-2 related x [Bax], and Caspase-3) and Nrf2 signaling pathway-related proteins (Nrf2 and heme oxygenase-1 [HO-1]) in brain tissue; immunofluorescence assay was used to measure the expression of Nrf2 inside and outside the nucleus of brain tissue cells. Results Compared with the I/R group, the ISP group had significant reductions in neurological deficit score, the percentage of cerebral infarct volume, the serum levels of IL-1β, TNF-α, and MDA, and the levels of Bax and Caspase-3 in brain tissue (t=5.76-18.39,P

Background : Remote ischemic postconditioning (RIPostC) may protect the brain from ischemia/reperfusion (I/R) injury. The association between RIPostC and obesity has not yet been extensively studied. Methods : Twelve-week-old male Zucker diabetic fatty (ZDF; n=68) and Zucker diabetic lean (ZDL; n=51) rats were subjected to focal cerebral ischemia for 90 minutes, followed by 24 hours of reperfusion. RIPostC was performed with 5-minute I/R cycles using a tourniquet on the right hind limb. Results : The results showed a negative association between obesity and neurological impairment in ischemic animals. We observed a 70% greater infarct size in ZDF rats compared with their lean counterparts, as evaluated by 2,3,5-triphenyltetrazolium chloride staining. To measure the total fragmented DNA in peripheral lymphocytes, comet assay was performed. Obese rats exhibited higher levels of DNA damage (by approximately 135%) in peripheral blood lymphocytes even before the induction of stroke. RIPostC did not attenuate oxidative stress in the blood in obese rats subjected to ischemia. Focal cerebral ischemia increased core and penumbra tissue glutamate release in the brain and decreased it in the blood of ischemic ZDL rats, and these changes improved following RIPostC treatment. However, changes in blood and tissue glutamate content were not detected in ischemic ZDF rats or after RIPostC intervention. Conclusion : Our findings suggest that obese animals respond more severely to ischemia-reperfusion brain injury. However, obese animals did not achieve neuroprotective benefits of RIPostC treatment.

Background: Remote ischemic postconditioning (RIPostC) may protect the brain from ischemia/reperfusion (I/R) injury. The association between RIPostC and obesity has not yet been extensively studied. Methods: Twelve-week-old male Zucker diabetic fatty (ZDF; n=68) and Zucker diabetic lean (ZDL; n=51) rats were subjected to focal cerebral ischemia for 90 minutes, followed by 24 hours of reperfusion. RIPostC was performed with 5-minute I/R cycles using a tourniquet on the right hind limb. Results: The results showed a negative association between obesity and neurological impairment in ischemic animals. We observed a 70% greater infarct size in ZDF rats compared with their lean counterparts, as evaluated by 2,3,5-triphenyltetrazolium chloride staining. To measure the total fragmented DNA in peripheral lymphocytes, comet assay was performed. Obese rats exhibited higher levels of DNA damage (by approximately 135%) in peripheral blood lymphocytes even before the induction of stroke. RIPostC did not attenuate oxidative stress in the blood in obese rats subjected to ischemia. Focal cerebral ischemia increased core and penumbra tissue glutamate release in the brain and decreased it in the blood of ischemic ZDL rats, and these changes improved following RIPostC treatment. However, changes in blood and tissue glutamate content were not detected in ischemic ZDF rats or after RIPostC intervention. Conclusion: Our findings suggest that obese animals respond more severely to ischemia-reperfusion brain injury. However, obese animals did not achieve neuroprotective benefits of RIPostC treatment. [ABSTRACT FROM AUTHOR]

Purpose: Hepatic ischemic post-conditioning (IPOC) is shown to protect the liver from injury induced by ischemia/reperfusion (IR). However, the mechanism underlying this protection has remained elusive. The present study aimed to investigate the role of the interleukin 6-Janus kinase-signal transducers and activators of transcription (IL-6-JAK-STAT) pathway in the protective effect of hepatic IPOC against the IR-induced injury in the liver. Methods: Twenty-five rats were randomly divided into 5 groups of (1) sham-operated, (2) IR, (3) IR+hepatic IPOC, (4) IR+tofacitinib (TOFA), and (5) IR+TOFA+hepatic IPOC. The changes induced by IR and the effects of different treatments were assessed by enzyme release, histopathological observations, the serum level of IL-6, and the occurrence of apoptosis detected via the expression of the Bax/Bcl-2 ratio. Results: The hepatic IPOC improved the liver injury induced by IR as shown by histological changes, reduction of IL-6 level, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) compared to the IR group (P <0.001,> P <0.05,> P P<0.05).> Conclusion: It suggests that the protective effect of hepatic IPOC against IR-induced injury may be mediated by activating the IL-6-JAK-STAT pathway. [ABSTRACT FROM AUTHOR]

Ischemic postconditioning (I-PostC) has a protective effect against acute kidney injury (AKI) induced by limb ischemia–reperfusion (LIR); however, the exact mechanism remains to be elucidated. Our study aims to investigate the potential involvement of high-mobility group box 1 protein (HMGB1) and autophagy in renoprotection generated by I-PostC. A rat model of LIR-induced AKI was established and rats were randomly assigned to five groups: (i) sham-operated control, (ii) I/R, (iii) I/R + I-PostC, (iv) I/R + I-PostC + rapamycin (autophagy activator), and (v) I/R + I-PostC + 3-methyladenine (autophagy inhibitor). Morphological changes in the kidneys were assessed by histology, and ultrastructural changes in renal tubular epithelial cells and glomerular podocytes were observed by transmission electron microscopy. The levels of kidney function parameters, serum inflammatory factors, and autophagy markers were detected. The results showed that the levels of HMGB1, Beclin1, LC3-II/LC3-I, and inflammatory cytokines (TNF-α and IL-6) were significantly higher in the I/R group compared to the sham control in serum and in renal tissues. I-PostC significantly reduced the levels of HMGB1, Beclin1, LC3-II/LC3-I, and inflammatory cytokines in renal tissues and improved renal function. Renal histopathology and ultrastructural observations indicated that I-PostC alleviated renal tissue injury. In addition, rapamycin (autophagy activator) treatment increased the levels of inflammatory cytokine expression levels and decreased renal function, reversed the protective effect of I-PostC against LIR-induced AKI. In conclusion, I-PostC could play a protective role against AKI by regulating the release of HMGB1 and inhibiting autophagy activation. [ABSTRACT FROM AUTHOR]

Purpose: Ischemic postconditioning (IPostC) alleviates myocardial ischemia/reperfusion (IR) injury, but the protective effect is lost during diabetes. PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) is able to inactivate Akt. Our previous study found that PHLPP1 expression was upregulated in diabetic hearts. We presumed that the attenuation of myocardial injury by IPostC might be hindered by PHLPP1 overexpression in diabetic animals. Methods and results: Nondiabetic and diabetic mice were subjected to 45 min of ischemia followed by 2 h of reperfusion with or without IPostC. H9c2 cells were exposed to normal or high glucose and were subjected to 4 h of hypoxia followed by 4 h of reoxygenation with or without hypoxic postconditioning (HPostC). IPostC attenuated postischemic infarction, apoptosis, creatine kinase-MB, and oxidative stress, which were accompanied by increased p-Akt and decreased PHLPP1 expression and p-Mst1 in nondiabetic but not in diabetic mice. PHLPP1 knockdown or an Mst1 inhibitor reduced hypoxia/reoxygenation (HR)-induced cardiomyocyte damage in H9c2 cells exposed to normal glucose, but the effect was abolished by a PI3K/Akt inhibitor. HPostC attenuated HR-induced cardiomyocyte injury and oxidative stress accompanied by increased p-Akt as well as decreased PHLPP1 expression and p-Mst1 in H9c2 cells exposed to normal glucose but not high glucose. In addition, HPostC in combination with PHLPP1 knockdown or PHLPP1 knockdown alone reduced cell death and oxidative stress in H9c2 cells exposed to high glucose, which was hindered by PI3K/Akt inhibitor. Conclusion: IPostC prevented myocardial IR injury partly through PHLPP1/Akt/Mst1 signaling, and abnormalities in this pathway may be responsible for the loss of IPostC cardioprotection in diabetes. [ABSTRACT FROM AUTHOR]

IPoC possesses a preventive effect against IR injury in healthy myocardium, but IPoC's protective effect on atherosclerotic myocardium is controversial. The current investigation aims to determine whether IPoC remains protective in atherosclerotic myocardium subjected to ischemia-reperfusion (IR) injury; to explore the specific mechanisms by which IPoC exerts cardioprotection; to explore whether HIF-1 upregulation combined with IPoC could further the provide cardioprotection; and to gaze at the specific mechanism whereby combined treatment expert the cardioprotection. ApoE−/− mice fed with a high-fat diet (HFD) were used to develop a model of atherosclerosis. The myocardial IR model was induced by occlusion of the left anterior descending (LAD) artery for 45 min, followed by reperfusion for 120 min. The protection of IPoC in both healthy and atherosclerotic myocardium was evaluated by measuring oxidative stress, apoptosis, infarct size, pathology, mitochondrial dysfunction and morphology of myocardium. The specific mechanism by which IPoC exerts cardioprotection in healthy and atherosclerotic myocardium was observed by measuring the expression of proteins involved in HIF-1, APMK and RISK pathways. The effect of HIF-1α overexpression on the cardioprotection by IPoC was observed by intravenous AAV9 -HIF-1α injection. In healthy ischemic myocardium, IPoC exerted myocardial protective effects (antioxidant, anti-apoptosis, and improved mitochondrial function) through the activation of HIF-1, AMPK and RISK pathways. In atherosclerotic ischemic myocardium, IPoC exerted cardioprotection only through the activation of HIF-1 pathway; however, HIF-1 overexpression combined IPoC restored the activation of AMPK and RISK pathways, thereby further alleviating the myocardial IR injury. In the atherosclerotic state, the HIF-1 pathway is the intrinsic mechanism by which IPoC exerts cardioprotective effects. The combination of HIF-1 upregulation and IPoC has a significant effect in reducing myocardial injury, which is worth being promoted and advocated. In addition, HIF-1-AMPK and HIF-1-RISK may be two endogenous cardioprotective signalling pathways with great value, which deserve to be thoroughly investigated in the future. Figure A illustrates the mechanism through which IPoC guards the myocardium from ischemia-reperfusion (IR) injury in healthy myocardium.Figure B illustrates the mechanism through which IPoC guards the myocardium from IR injury in atherosclerotic myocardium.Figure C illustrates the mechanism through which HIF-1 overexpression and IPoC combined treatment exerts cardioprotection against IR injury in atherosclerotic myocardium. [Display omitted] • In normal myocardium, the cardioprotection of IPoC is mediated by activation of the HIF-1, AMPK, and RISK pathways. • In atherosclerotic myocardium IR, the AMPK and RISK pathways are impaired and fail to be activated by IPoC. • In atherosclerotic myocardial IR, IPoC can still exert considerable cardioprotection by activating HIF-1 pathway. • HIF-1 pathway per se has a potent cardioprotective effect in the setting of atherosclerosis. • HIF-1 overexpression and IPoC combined treatment restored the activation of AMPK and RISK pathway. • The HIF-AMPK/RISK cascade is the intrinsic cardioprotective signaling in the context of atherosclerosis. [ABSTRACT FROM AUTHOR]

The repetitive inflation–deflation of a blood pressure cuff on a limb is known as remote limb ischemic postconditioning (RIPostC). It prevents brain damage induced by acute ischemia stroke (AIS). Pyroptosis, executed by the pore‐forming protein gasdermin D (GSDMD), is a type of regulated cell death triggered by proinflammatory signals. It contributes to the pathogenesis of ischemic brain injury. However, the effects of RIPostC on pyroptosis following AIS remain largely unknown. In our study, linear correlation analysis confirmed that serum GSDMD levels in AIS patients upon admission were positively correlated with NIHSS scores. RIPostC treatment significantly reduced GSDMD level compared with patients without RIPostC at 3 days post‐treatment. Besides, middle cerebral artery occlusion (MCAO) surgery was performed on C57BL/6 male mice and RIPostC was induced immediately after MCAO. We found that RIPostC suppressed the activation of NLRP3 inflammasome to reduce the maturation of GSDMD, leading to decreased pyroptosis in microglia after AIS. Hepatocyte growth factor (HGF) was identified using the high throughput screening. Importantly, HGF siRNA, exogenous HGF, and ISG15 siRNA were used to reveal that HGF/ISG15 is a possible mechanism of RIPostC regulation in vivo and in vitro. [ABSTRACT FROM AUTHOR]

Pulmonary ischemia and reperfusion (I/R) injury occurs in many clinical conditions and causes severe damage to the lungs. Diabetes mellitus (DM) predisposes to pulmonary I/R injury. We previously found that remote liver ischemia preconditioning protected lungs against pulmonary I/R injury. The aim of the present study was to investigate whether remote liver ischemic postconditioning (RLIPost) attenuates pulmonary damage induced by I/R injury in non-diabetic or diabetic rats. Male Sprague-Dawley rats were assigned into non-diabetic and diabetic groups. All rats except for the sham were exposed to 45 min of left hilum occlusion followed by 2 h of reperfusion. RLIPost was conducted at the onset of pulmonary reperfusion by four cycles of 5 min of liver ischemia and reperfusion. Lung injury was assessed by the wet/dry weight ratio, pulmonary oxygenation, histopathological changes, apoptosis and the expression of inflammatory cytokines. Reperfusion-associated protein phosphorylation states were determined. RLIPost offered strong pulmonary-protection in both non-diabetic and diabetic rats, as reflected in reduced water content and pulmonary structural damage, recovery of lung function, inhibition of apoptosis and inflammation after ischemia-reperfusion. RLIPost induced the activation of pulmonary STAT-3, a key component in the SAFE pathway, but not activation of the proteins in the RISK pathway, in non-diabetic rats. In contrast, RLIPost-induced pulmonary protection in diabetic lungs was independent of SAFE or RISK pathway activation. These results demonstrate that RLIPost exerts pulmonary protection against I/R-induced lung injury in non-diabetic and diabetic rats. The underlying mechanism for protection may be different in non-diabetic (STAT-3 dependent) versus diabetic (STAT-3 independent) rats.

Background: In recent years, stroke and ischemia–reperfusion injury has motivated researchers to find new ways to reduce the complications. Although reperfusion is essential for brain survival, it is like a double-edged sword that may cause further damage to the brain. Ischemic postconditioning (IPostC) refers to the control of blood flow in postischemia–reperfusion that can reduce ischemia-reperfusion injuries. Materials and Methods: Articles were collected by searching for the terms: Ischemic postconditioning and neuroprotective and ischemic postconditioning and hyperperfusion. Suitable articles were collected from electronic databases, including ISI Web of Knowledge, Medline/PubMed, ScienceDirect, Embase, Scopus, Biological Abstract, Chemical Abstract, and Google Scholar. Results: New investigations show that IPostC has protection against hyperperfusion by reducing the amount of blood flow during reperfusion and thus reducing infarction volume, preventing the blood–brain barrier damage, and reducing the rate of apoptosis through the activation of innate protective systems. Numerous mechanisms have been suggested for IPostC, which include reduction of free radical production, apoptosis, inflammatory factors, and activation of endogenous protective pathways. Conclusion: It seems that postconditioning can prevent damage to the brain by reducing the flow and blood pressure caused by hyperperfusion. It can protect the brain against damages such as stroke and hyperperfusion by activating various endogenous protection systems. In the present review article, we tried to evaluate both useful aspects of IPostC, neuroprotective effects, and fight against hyperperfusion.

AbstractIschemic postconditioning (I-PostC) has a protective effect against acute kidney injury (AKI) induced by limb ischemia–reperfusion (LIR); however, the exact mechanism remains to be elucidated. Our study aims to investigate the potential involvement of high-mobility group box 1 protein (HMGB1) and autophagy in renoprotection generated by I-PostC. A rat model of LIR-induced AKI was established and rats were randomly assigned to five groups: (i) sham-operated control, (ii) I/R, (iii) I/R + I-PostC, (iv) I/R + I-PostC + rapamycin (autophagy activator), and (v) I/R + I-PostC + 3-methyladenine (autophagy inhibitor). Morphological changes in the kidneys were assessed by histology, and ultrastructural changes in renal tubular epithelial cells and glomerular podocytes were observed by transmission electron microscopy. The levels of kidney function parameters, serum inflammatory factors, and autophagy markers were detected. The results showed that the levels of HMGB1, Beclin1, LC3-II/LC3-I, and inflammatory cytokines (TNF-α and IL-6) were significantly higher in the I/R group compared to the sham control in serum and in renal tissues. I-PostC significantly reduced the levels of HMGB1, Beclin1, LC3-II/LC3-I, and inflammatory cytokines in renal tissues and improved renal function. Renal histopathology and ultrastructural observations indicated that I-PostC alleviated renal tissue injury. In addition, rapamycin (autophagy activator) treatment increased the levels of inflammatory cytokine expression levels and decreased renal function, reversed the protective effect of I-PostC against LIR-induced AKI. In conclusion, I-PostC could play a protective role against AKI by regulating the release of HMGB1 and inhibiting autophagy activation.

Background and Objectives: Allergic contact dermatitis is a common type IV hypersensitivity reaction characterised by redness, itching, oedema and thickening of the skin. It occurs in about 7% of the population and its incidence is increasing. It has been observed that the preconditioning of tissues by exposing them to transient ischemia increases resistance to subsequent permanent ischemia, and this phenomenon is called ischemic preconditioning. It has been shown that conditioning in one organ can also protect other organs. The protective effect of remote ischemic preconditioning is thought to be based on the induction of anti-inflammatory responses. The aim of this project was to investigate the anti-inflammatory and antipruritic effects of remote ischemic postconditioning in a mouse model of experimental allergic contact dermatitis. Methods: Experimental allergic contact dermatitis was induced with 1-fluoro-2,4-dinitrobenzene. Remote ischemic postconditioning was performed at 3 and 25 h after the challenge. Ear thickness and number of scratches 24 and 48 h after challenge, as well as cytokine levels and the infiltration of mast cells, neutrophils, CD4+ and CD8+ T lymphocytes in serum and ear tissue at 48 h were measured to determine the effect of RIPsC. Results: Remote ischemic postconditioning decreased ear thickness, one of the symptoms of allergic contact dermatitis (p < 0.0001). It had no significant effect on the number of scratches. It reduced serum IL-17 levels (p < 0.01). It alleviated local inflammation by suppressing CD8+ T lymphocyte and neutrophil infiltration. Conclusions: It was concluded that remote ischemic postconditioning may alleviate the symptoms of allergic contact dermatitis by suppressing CD8+ T lymphocyte and neutrophil infiltration and reducing IL-17 secretion. [ABSTRACT FROM AUTHOR]

Background and purpose: Experimental studies suggest that ischemic postconditioning interferes with cell death mechanisms and reduces infarction during the acute phase after focal cerebral ischemia. Postconditioning may be a practically feasible way to promote stroke recovery, but many drawbacks prevent its clinical translation. First, all existing studies are mostly on acute 24 h outcomes. Second, the mechanisms of protection and augmented long-term benefits remain unclear. Our study aims to define some of the mechanisms that explain long-term benefits of improved recovery. Methods: Male Sprague-Dawley rats were subjected to 100-min transient middle cerebral artery occlusion (MCAO) or postconditioning (100-min middle cerebral artery occlusion plus 10-min reperfusion plus 10-min reocclusion). After 3 days or 2 weeks, infarct volumes, western blot, and immunohistochemical markers of neurogenesis and angiogenesis were quantified. Fluorocitrate (FC) or saline were administrated ICV (intraventricular injection) every other day starting on day 5 after focal cerebral ischemia, animals were recovered for 2 weeks. Results: After postconditioning BDNF protein expression levels increased compared to animals subjected to MCAO. Immunostaining showed that BDNF increased specifically in astrocytes. Moreover, when astrocytes were metabolically inhibited by fluorocitrate the postconditioning neuroprotective effect together with the postconditioning-dependent new angiogenesis and neurogenesis, were no longer observed. Conclusion: These results suggest for the first time that therapeutic effects of postconditioning may involve the promotion of neurogenesis and angiogenic remodeling, via BDNF released by astrocytes, during the recovery phase after focal cerebral ischemia. [ABSTRACT FROM AUTHOR]

Background: Remote ischemic postconditioning (RIPoC) is induced by several cycles of brief, reversible, mechanical blood flow occlusion, and reperfusion of the distal organs thereby protecting target organs. We investigated if RIPoC ameliorated liver injury in a lipopolysaccharide (LPS)-induced endotoxemic rats. Methods: Protocol 1) Rats were administered LPS and samples collected at 0, 2, 6, 12, and 18 h. 2) After RIPoC at 2, 6, and 12 h (L+2R+18H, L+6R+18H, and L+12R+18H), samples were analyzed at 18 h. 3) RIPoC was performed at 2 h, analysis samples at 6, 12, 18 h (L+2R+6H, L+2R+12H, L+2R+18H), and RIPoC at 6 h, analysis at 12 h (L+6R+12H). 4) Rats were assigned to a control group while in the RIPoC group, RIPoC was performed at 2, 6, 10, and 14 h, with samples analyzed at 18 h. Results: Protocol 1) Liver enzyme, malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), and nuclear factor-κB (NF-κB) levels increased while superoxide dismutase (SOD) levels decreased over time. 2) Liver enzyme and MDA levels were lower while SOD levels were higher in L+12R+18H and L+6R+18H groups when compared with L+2R+18H group. 3) Liver enzyme and MDA levels were lower while SOD levels were higher in L+2R+6H and L+6R+12H groups when compared with L+2R+12H and L+2R+18H groups. 4) Liver enzyme, MDA, TNF-α, and NF-κB levels were lower while SOD levels were higher in RIPoC group when compared with control group. Conclusions: RIPoC attenuated liver injury in the LPS-induced sepsis model by modifying inflammatory and oxidative stress response for a limited period. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction and objectives: Ischemic postconditioning (iPost, coronary intermittent re-occlusion maneuvers immediately after PCI-mediated reperfusion) has been proposed to limit infarct size (IS). However, a few experimental and clinical contradictory results have been reported. We hypothesized that iPost cardioprotection is affected by the duration of ischemia. Our objective was to assess IS in the presence/absence of iPost in a pig model of myocardial infarction of variable ischemia duration. Methods: Large white pigs (n = 38) underwent angioplasty balloon-induced coronary ischemia followed by reperfusion. Two set of experiments were carried out: intermediate (30 min) and prolonged (40 min) ischemia. In both, pigs were allocated on a 1:1 ratio to receive iPost (4 cycles of “1 min balloon inflation followed by 1 min deflation” upon reperfusion) or control. Animals underwent contrast-enhanced multiparametric cardiac magnetic resonance scan on day 7. Primary outcome measure was cardiac magnetic resonance-based IS (% of left ventricular mass). The interaction between treatment allocation and ischemia duration was assessed using a 2-way ANOVA test. Results: iPost was not associated with smaller IS in any of the ischemia duration protocols (intermediate ischemia: 0.3% [0.0–3.9] vs 0.9% [0.0–2.6] in iPost and control, respectively; P = .378; long ischemia: 31.1% [27.3–32.8] vs 27.3% [25.1–27.5]; P = .248). When both ischemia-duration protocols were combined, iPost was not associated with smaller IS (3.9% [0.0–30.9] vs 4.6% [0.2–25.1]; P = .672). T1 relaxation times were longer in animals undergoing iPost compared to controls (1306.2 ms [1190.7–1492.7] vs 1240.7 ms [1167.1–1304.5]; P = .024). Conclusions: In a pig model of reperfused myocardial infarction of variable ischemia duration, iPost failed to reduce IS. T1 relaxation times were longer in animals undergoing iPost indicative of the potential harm involved in this procedure.

Objective • To assess the effect of a regional collaborative network on the treatment of ST-elevation myocardial infarction (STEMI) patients first admitted to nonpercutaneous coronary intervention (PCI) hospitals. Methods • Using data from Kunshan Hospital of Traditional Chinese Medicine’s chest pain center database, patients were grouped based on the establishment of the regional collaborative rescue network. Key timepoints and in-hospital complications were analyzed. Results •A total of 152 ST-elevation myocardial infarction patients were included in the study. Compared to control group, symptom-to-balloon time (S-B), time of first medical contact to balloon and inter-hospital referral time in observation group were significantly shorter [(314.03 ± 209.26) min vs (451.27 ± 290.44) min, P = .001], [(115.32 ± 54.73) min vs (191.67 ± 130.30) min, P = .001], [(55.09 ± 37.23) min vs (112.67 ± 95.90) min, P = .001], but time of symptom to first medical contact were not statistically significant[(210.27±217.07) min vs (239.61 ± 200.92) min, P = .136].The incidence of heart failure and total complications during hospitalization decreased [7 (8.14%) vs 13 (19.70%), P = .037] and [14 (16.28%) vs 24 (36.36%), P = .004]. However no statistically significant difference were observed in rate of death during hospitalization [2 (2.33%) vs 3 (4.55%), P = .450], ventricular fibrillation [2 (2.33%) vs 3 (4.55%), P = .450], left ventricular thrombosis [2 (2.33%) vs 4 (6.06%), P = .244] and recurrent myocardial infarction[1 (1.16%) vs 1 (1.52%), P = .851]. Conclusions • The regional cooperative rescue network notably reduces ischemic and referral times for STEMI patients, lowering the incidence of heart failure during their hospital stay. [ABSTRACT FROM AUTHOR]

BACKGROUND: Ischemic postconditioning can alleviate myocardial ischemia-reperfusion injury, but the specific mechanism is not clear. OBJECTIVE: To investigate the mechanism of long non-coding RNA (lncRNA) MALAT1 in the reduction of autophagy levels in aging myocardium induced by ischemic postconditioning. METHODS: Twenty-seven Sprague-Dawley rats aged 22-24 months were randomly divided into three groups, with nine rats in each group: sham operation, ischemia-reperfusion, and ischemic postconditioning groups. Morphological changes of myocardial tissue were observed by hematoxylin-eosin staining and Masson staining. Rat myocardial cells (H9C2) were induced in vitro with 8 mg/mL D-galactose for 9 days and then divided into normoxia, hypoxia-reoxygenation, and hypoxia postconditioning groups. Western blot was used to detect the protein expression levels of LC3II/I and p62. Fluorescence quantitative PCR was used to detect the expression of lncRNA MALAT1 in aging myocardium and aging cardiomyocytes. Autophagy double-labeled adenovirus (RFP-GFP-LC3) was used to observe the changes of autophagic flux in aging cardiomyocytes. lncRNA MALAT1 interference fragment and overexpression plasmid were transfected into aging cardiomyocytes and the protein expression levels of LC3II/I and p62 were detected by western blot. RESULTS AND CONCLUSION: Compared with the ischemia-reperfusion group, the myocardial tissue structure of the ischemic postconditioning group was basically clear, the nucleus was intact, and the deposition of blue collagen fibers in the myocardial tissue was reduced. Compared with the ischemia-reperfusion group, the expression of LC3II/I was decreased and the expression of p62 was increased in the ischemic postconditioning group (P < 0.05). Compared with the hypoxia-reperfusion group, the expression of LC3II/I was decreased (P < 0.01) and the expression of p62 was increased (P < 0.05) in the hypoxia postconditioning group, and the number of intracellular autophagosomes and autophagolysosomes was decreased (P < 0.05). Compared with the ischemiareperfusion group, the expression of MALAT1 in the aging myocardial tissue was decreased the ischemic postconditioning group (P < 0.01); compared with the hypoxia-reperfusion group, the expression of MALAT1 in aging cardiomyocytes was decreased in the hypoxic postconditioning group (P < 0.01). Compared with the hypoxia postconditioning+si-NC group, the expression of LC3II/I was decreased and the expression of p62 was increased in the hypoxia postconditioning +si-lncRNA MALAT1 (P < 0.01); compared with the hypoxia postconditioning+ad-NC group, the expression of LC3II/I was increased and the expression of p62 was decreased in the hypoxia postconditioning+ad-lncRNA MALAT1 group (P < 0.01). To conclude, the lncRNA MALAT1 mediated reduction of autophagy levels is an important mechanism underlying the protective effect of ischemic postconditioning in aging myocardium. [ABSTRACT FROM AUTHOR]

Delayed neuronal damage can be caused or aggravated after cerebral ischemia–reperfusion (I/R) injury. Recent studies have shown that glymphatic system dysfunction after cerebral ischemia–reperfusion injury is involved in ischemic brain edema and neuroinflammation, thereby regulating cerebral ischemia–reperfusion injury. The aim of this study is to investigate the changes of glymphatic system after cerebral ischemia–reperfusion injury and whether limb remote ischemic postconditioning (LRIP) can improve the function of glymphatic system to protect the brain. To establish a focal brain I/R injury mouse model, this study utilized the middle cerebral artery occlusion/reperfusion (MCAO/R) method. The present study classified eight-week-old C57BL/6 male mice into three groups. The changes in glymphatic function in different periods of ischemia and reperfusion were analyzed through immunofluorescence, transmission electron microscopy (TEM), and Western-Blot (WB) assays. The contents of the evaluation included cerebrospinal fluid flow, swelling degree of brain tissue, aquaporin-4 (AQP4) expression and polarization, and amyloid-β (Aβ) excretion. In the early stages of cerebral ischemia, cerebrospinal fluid (CSF) flow is disturbed, accompanied by a decrease in AQP4 polarization. The polarity of AQP4 decreased from 12 h to 72 h of reperfusion, the Aβ deposition. LRIP can increase the expression of β-DG and AQP4 polarization, reduce the deposition of Aβ, improve the function of the glymphatic system, and reduce the expression of AQP4 to play A protective role in brain. Glymphatic system impaired after cerebral ischemia–reperfusion injury in mice. LRIP may play a neuroprotective role by improving glymphatic function after I/R. [ABSTRACT FROM AUTHOR]

AIM: To evaluate the role of nucleotide-binding oligomerization domain-like receptor protein 3 （NLRP3） inflammasome-mediated pyroptosis in rat lung ischemia/reperfusion injury （LIRI） and the intervention effects of ischemic post-conditioning （I-post-C） treatment. METHODS: Twenty SPF grade male SD rats aged 6 to 8 weeks were randomly divided into 4 groups: control group, LIRI group, I-post-C group, and INF39+LIRI group. After the experiment, the rats were sacrificed, and tissue samples from the left lung were harvested. The morphological changes of the lung tissues were examined by ordinary light microscopy. The level of reactive oxygen species （ROS） was evaluated by dihydroethidium staining. The changes of oxidative stress indicators malondialdehyde（ MDA）, glutathione（ GSH） and myeloperoxidase（ MPO）, as well as the level of caspase-1, were detected using commercially available kits. The levels of interleukin-1β （IL-1β） and IL-18 in the lung tissue were detected by ELISA. The mRNA levels of NLRP3, IL-1β, IL-18 and thioredoxin-interacting protein （TXNIP） were detected by RT-qPCR. The protein levels of NLRP3, N-terminal fragment of gasdermin D （GSDMD-N）, cleaved caspase-1 and TXNIP were detected by Western blot. The TXNIP expression was also detected by immunofluorescence. RESULTS: The surface of the left lung in LIRI group was interspersed with dark red and light red, with brittle texture, obvious rupture of the alveolar wall, deformation and collapse of the alveoli, infiltration of neutrophils and red blood cells, and interstitial edema. The LIRI caused the production of a large number of ROS （P<0. 01）. Compared with control group, LIRI group showed significant increases in MDA content of and MPO activity, and a significant decrease in GSH content （P<0. 01）. The mRNA and protein levels of TXNIP were significantly up-regulated （P<0. 05）. The mRNA levels of IL-1β and IL-18 in the lung tissue were noticeably increased （P<0. 01）, and the mRNA and protein levels of NLRP3 were significantly increased （P<0. 05）. The protein levels of GSDMD-N and cleaved caspase-1 were significantly increased, and the activity of caspase-1 in the lung tissue was dramatically increased （P< 0. 01）. Compared with LIRI group, lung tissue injury in I-post-C group was significantly attenuated. The ROS accumulation was significantly reduced, the MDA content and MPO activity in I-post-C group were decreased （P<0. 05）, and the content of GSH was increased significantly （P<0. 01）. The mRNA and protein levels of TXNIP were down-regulated （P< 0. 05）. Compared with LIRI group, the mRNA level and tissue content of IL-1β and IL-18 in the lung tissue of I-post-C and INF39+LIRI groups were significantly decreased （P<0. 05）. The NLRP3 mRNA and protein levels in the lung tissue were significantly down-regulated, and the protein levels of GSDMD-N and cleaved caspase-1 were significantly decreased （P<0. 05）. CONCLUSION: The I-post-C alleviates LIRI in rats, and its mechanism may be related to the regulation of ROS-TXNIP-NLRP3-GSDMD signaling pathway. [ABSTRACT FROM AUTHOR]

Remote Ischemic Postconditioning (RIPostC) has become a research hotspot due to its protective effect on the brain in clinical studies related to ischemic stroke. The purpose of this study is to investigate the protective effect of RIPostC after ischemic stroke in rats. The middle cerebral artery occlusion/reperfusion (MCAO/R) model was established by the wire embolization method. RIPostC was obtained by inducing temporary ischemia in the hind limbs of rats. First, based on the results of short-term behavioral measures and long-term neurological function experiments, RIPostC was found to have a protective effect on the MCAO/R model and to improve neurological recovery in rats. Compared to the sham group, RIPostC upregulated the expression levels of C-X-C motif chemokine receptor 4(CXCR4) in the brain and stromal cell-derived factor-1(SDF-1α) in peripheral blood. In addition, RIPostC upregulated CXCR4 expression on CD34 + stem cells in peripheral blood in flow cytometric assays. Meanwhile, according to the results of EdU/DCX co-staining and CD31 staining, it was found that the effect of RIPostC on ameliorating brain injury via SDF-1α/CXCR4 signaling axis may be associated with vascular neogenesis. Finally, after inhibiting the SDF-1α/CXCR4 signaling axis using AMD3100(Plerixafor), we found that the neuroprotective effect of RIPostC was diminished. Taken together, RIPostC can improve neurobehavioral damage induced by MCAO/R in rats, and its mechanism may be related to SDF-1α/CXCR4 signaling axis. Therefore, RIPostC can be used as an intervention strategy for stroke. SDF-1α/CXCR4 signaling axis can also be a potential target for intervention. • RIPostC ameliorates ischemic stroke injury in rats. • SDF-1α/CXCR4 levels were upregulated after RIPostC in post-stroke rats. • RIPostC improved neurogenesis and angiogenesis in rats after ischemic stroke. • Inhibiting of SDF-1α/CXCR4 signaling axis could reverse the protection effects of RIPostC after stroke in rats. [ABSTRACT FROM AUTHOR]

Background and Aims: A potential strategy to treat ischemic stroke may be the application of repeated remote ischemic postconditioning (rIPostC). This consists of several cycles of brief periods of limb ischemia followed by reperfusion, which can be applied by inflating a simple blood pressure cuff and subsequently could result in neuroprotection after stroke. Methods: Adult patients admitted with an ischemic stroke in the past 24 h were randomized 1:1 to repeated rIPostC or sham-conditioning. Repeated rIPostC was performed by inflating a blood pressure cuff around the upper arm (4 × 5 min at 200 mm Hg), which was repeated twice daily during hospitalization with a maximum of 4 days. Primary outcome was infarct size after 4 days or at discharge. Secondary outcomes included the modified Rankin Scale (mRS)-score after 12 weeks and the National Institutes of Health Stroke Scale (NIHSS) at discharge. Results: The trial was preliminarily stopped after we included 88 of the scheduled 180 patients (average age: 70 years, 68% male) into rIPostC (n = 40) and sham-conditioning (n = 48). Median infarct volume was 2.19 mL in rIPostC group and 5.90 mL in sham-conditioning, which was not significantly different between the two groups (median difference: 3.71; 95% CI: −0.56 to 6.09; p = 0.31). We found no significant shift in the mRS score distribution between groups. The adjusted common odds ratio was 2.09 (95% CI: 0.88–5.00). We found no significant difference in the NIHSS score between groups (median difference: 1.00; 95% CI: −0.99 to 1.40; p = 0.51). Conclusion: This study found no significant improvement in infarct size or clinical outcome in patients with an acute ischemic stroke who were treated with repeated remote ischemic postconditioning. However, due to a lower-than-expected inclusion rate, no definitive conclusions about the effectiveness of rIPostC can be drawn [ABSTRACT FROM AUTHOR]

Ischemic postconditioning (IPost) represents short periods of nonlethal ischemia–reperfusion performed at the onset of reperfusion. Studies have shown that IPost involves various biological processes such as cell proliferation, apoptosis, and pyroptosis and can activate complex signaling pathways. CCL12 is a critical mediator in the inflammatory process after tissue injury. In the present study, we examined the potential actions of CCL12-mediated signaling pathways in cardioprotection after IPost using a cardiomyocyte model. By applying the bioinformatics analysis, we found that CCL12 was upregulated in the rat heart tissues after I/R injury, and the expression level of CCL12 was restored in rats with IPost. The in vitro studies showed that CCL12 and CCR2 expression levels were upregulated in the hypoxia/reoxygenation (H/R)-induced H9C2 cells, which was attenuated in the H/R + hypoxia post-conditioning (PostC) group. The functional assays showed that H/R treatment reduced cell viability, increased cell apoptosis, and promoted fibrosis and pyroptosis of H9C2 cells, which was attenuated in the H/R + PostC group. Overexpression of CCL12 impaired the protective action of hypoxia post-conditioning in the H9C2 cells. Further mechanistic studies showed that miR-144-5p could directly target the 3′ untranslated region of CCL12. Overexpression of miR-144-5p markedly repressed the expression levels of CCL12 and CCR2 in H9C2 cells, while miR-144-5p inhibition had the opposite effects. Furthermore, the inhibition of miR-144-5p reduced the cell viability, increased cell apoptosis, and enhanced fibrosis and pyroptosis of H9C2 cells after H/R or H/R + PostC treatment. In conclusion, CCL12 was downregulated in cardiomyocytes following ischemic postconditioning, and CCL12 overexpression impaired the cardioprotective actions of ischemic postconditioning by reducing cell viability, enhancing cell apoptosis, fibrosis, and pyroptosis. Further mechanistic evidence revealed that CCL12 was a direct target of miR-144-5p, and miR-144-5p/CCL12/CCR2 signaling may represent a critical pathway in mediating the cardioprotective effects of ischemic postconditioning. [ABSTRACT FROM AUTHOR]

Caveolae-associated signaling toward mitochondria contributes to the cardioprotective mechanisms against ischemia-reperfusion (I/R) injury induced by ischemic postconditioning. In this work, we evaluated the role that the actin-cytoskeleton network exerts on caveolae-mitochondria communication during postconditioning. Isolated rat hearts subjected to I/R and to postconditioning were treated with latrunculin A, a cytoskeleton disruptor. Cardiac function was compared between these hearts and those exposed only to I/R and to the cardioprotective maneuver. Caveolae and mitochondria structures were determined by electron microscopy and maintenance of the actin-cytoskeleton was evaluated by phalloidin staining. Caveolin-3 and other putative caveolae-conforming proteins were detected by immunoblot analysis. Co-expression of caveolin-3 and actin was evaluated both in lipid raft fractions and in heart tissue from the different groups. Mitochondrial function was assessed by respirometry and correlated with cholesterol levels. Treatment with latrunculin A abolishes the cardioprotective postconditioning effect, inducing morphological and structural changes in cardiac tissue, reducing F-actin staining and diminishing caveolae formation. Latrunculin A administration to post-conditioned hearts decreases the interaction between caveolae-forming proteins, the co-localization of caveolin with actin and inhibits oxygen consumption rates in both subsarcolemmal and interfibrillar mitochondria. We conclude that actin-cytoskeleton drives caveolae signaling to mitochondria during postconditioning, supporting their functional integrity and contributing to cardiac adaption against reperfusion injury. [ABSTRACT FROM AUTHOR]

Objective: To explore the effect of ischemic postconditioning on myocardial ischemia-reperfusion-induced acute lung injury (ALI). Methods: Forty adult male C57BL/6 mice were randomly divided into sham operation group (SO group), myocardial ischemia-reperfusion group (IR group), ischemic preconditioning group (IPRE group) and ischemic postconditioning group (IPOST group) (10 mice in each group). Anterior descending coronary artery was blocked for 60 min and then reperfused for 15 min to induce myocardial IR. For the IPRE group, 3 consecutive cycles of 5 min of occlusion and 5 minutes of reperfusion of the coronary arteries were performed before ischemia. For the IPOST group, 3 consecutive cycles of 5 min reperfusion and 5 minutes of occlusion of the coronary arteries were performed before reperfusion. Pathological changes of lung tissue, lung wet-to-dry (W/D) weight ratio, inflammatory factors, oxidative stress indicators, apoptosis of lung cells and endoplasmic reticulum stress (ERS) protein were used to evaluate lung injury. Results: After myocardial IR, lung injury worsened significantly, manifested by alveolar congestion, hemorrhage, structural destruction of alveolar septal thickening, and interstitial neutrophil infiltration. In addition, lung W/D ratio was increased, plasma inflammatory factors, including interleukin (IL)-6, tumor necrosis factor (TNF)-a, and IL-17A, were increased, malondialdehyde (MDA) activity of lung tissue was increased, and superoxide dismutase (SOD) activity was decreased after myocardial IR. It was accompanied by the increased protein expression levels of ERS-related protein glucose regulatory protein 78 (GRP78), CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), and caspase-12, and the increased apoptotic indices of lung tissues. Conclusion: IPOST can effectively improve myocardial IR-induced ALI by inhibiting ERS-induced apoptosis of alveolar epithelial cells. [ABSTRACT FROM AUTHOR]

Background: Previous experimental studies have found that ischemic post-conditioning exhibits neuroprotective effects by alleviating ischemiareperfusion injury in an acute ischemic stroke model, and its efficacy is thought to be related to the duration of ischemic post-conditioning. However, ischemic post-conditioning has not been used in patients with acute ischemic stroke. This study aims to determine the safety, tolerability, and maximum tolerable duration of ischemic post-conditioning in patients with acute ischemic stroke receiving mechanical thrombectomy. Methods: Patients with acute ischemic stroke with unilateral middle cerebral artery M1 segment occlusion eligible for mechanical thrombectomy will be enrolled. We adopt a 3 + 3 dose-escalation design with a duration escalation schedule of 0, 1, 2, 3, 4, and 5 min × 4 cycles for the ischemic post-conditioning study. After successful reperfusion following mechanical thrombectomy, the balloon for ischemic post-conditioning will be inflated at the site proximal to the culprit lesion four times for 0-5 min with low-pressure (3-4 atmospheres) inflations, each separated by 0-5 min of reflow. We pre-defined the major responses (vessel perforation or rupture, reocclusion of the culprit vessel after ischemic post-conditioning, vessel dissection, severe vasospasm, ischemic post-conditioning related thrombotic events, and rupture of the balloon used for ischemic post-conditioning) as the stopping rules. Each patient will undergo a rigorous evaluation to determine the safety, tolerability, and maximum tolerable duration of ischemic post-conditioning. Discussion: This will be the first clinical study to ascertain the safety and tolerability of ischemic post-conditioning in patients with acute ischemic stroke receiving mechanical thrombectomy. The maximum tolerable duration obtained in this study will also serve as a starting point for future studies on the efficacy of ischemic post-conditioning. [ABSTRACT FROM AUTHOR]

Background: The diabetic heart exhibits a high sensitivity to ischaemia/reperfusion (I/R) injury. Diabetes mellitus (DM) can affect the efficacy of cardioprotective interventions and reduce the therapeutic potential of existing treatment options. This study aimed to investigate the feasibility of shifting from monotherapy to combination therapy in diabetic myocardial I/R injury.Methods: 6-8 week rats were randomized into 10 groups: sham, I/R, ischaemia postconditioning (I-Post), nicorandil (Nic), combination therapy (I-Post + Nic), DM sham, DM I/R, DM I-Post, DM Nic and DM I-Post + Nic. The extent of myocardial injury was clarified by measuring CK-MB and NO levels in plasma, ROS content in myocardial tissues, and TTC/Evans Blue staining to assess the area of myocardial infarction. Pathological staining of cardiac tissue sections were performed to clarify the structural changes in myocardial histopathology. Finally, Western blotting was performed to detect the phosphorylation levels of some key proteins in the PI3K/Akt signalling pathway in myocardial tissues.Results: We confirms that myocardial injury in diabetic I/R rats remained at a high level after treatment with I-Post or nicorandil alone. I-Post combined with nicorandil showed better therapeutic effects in diabetic I/R rats, and the combined treatment further reduced the area of myocardial injury in diabetic I/R rats compared with I-Post or nicorandil treatment alone (P < 0.001), as well as the levels of the myocardial injury markers CK-MB and ROS (P < 0.001); it also significantly increased plasma NO levels. Pathological staining also showed that diabetic rats benefited significantly from the combination therapy. Further mechanistic studies confirmed this finding. The protein phosphorylation levels of PI3K/Akt signalling pathway in the heart tissue of diabetic I/R rats were significantly higher after the combination treatment than after one treatment alone (all P < 0.05).Conclusion: I-Post combined with nicorandil treatment maintains effective cardioprotection against diabetic myocardial I/R injury by activating the PI3K/Akt signalling pathway. [ABSTRACT FROM AUTHOR]

Background Despite therapeutic hypothermia, neonates with hypoxic–ischemic encephalopathy still develop neurological disabilities. We have previously investigated neuroprotection by remote ischemic postconditioning (RIPC) in newborn piglets following hypoxia–ischemia (HI). The aim of this study was to further investigate potential effects of RIPC on cerebral immunohistochemical markers related to edema, apoptosis, and angiogenesis. Methods Brain expression of aquaporin 4, caspase-3, B-cell lymphoma 2, and vascular endothelial growth factor was analyzed by immunohistochemistry in 23 piglets, randomly selected from a larger study of RIPC after HI. Twenty animals were subjected to 45 minutes of HI and randomized to treatment with and without RIPC, while three animals were randomized to sham procedures. RIPC was conducted by four conditioning cycles of 5-minute ischemia and reperfusion. Piglets were euthanized 72 hours after the HI insult. Results Piglets subjected to HI treated with and without RIPC were similar at baseline and following the HI insult. However, piglets randomized to HI alone had longer duration of low blood pressure during the insult. We found no differences in the brain expression of the immunohistochemical markers in any regions of interest or the whole brain between the two HI groups. Conclusion RIPC did not influence brain expression of markers related to edema, apoptosis, or angiogenesis in newborn piglets at 72 hours after HI. These results support previous findings of limited neuroprotective effect by this RIPC protocol. Our results may have been affected by the time of assessment, use of fentanyl as anesthetic, or limitations related to our immunohistochemical methods. [ABSTRACT FROM AUTHOR]

Wang, Jian, Cheng-Ying Yan, Wu Wang, and Tian-Zhen Wang. Preventive effect of moderate altitude on non-culprit lesion (NCL) progression in patients with acute myocardial infarction. High Alt Med Biol. 23:345–351, 2022. Background: Ischemic postconditioning may prevent NCL progression in patients with acute myocardial infarction. Moderate altitude (1,500–2,500 m) resembles ischemic postconditioning; however, the preventive effect of moderate altitude on NCL progression is unknown. Methods: We investigated the preventive effect of moderate altitude on NCL progression in patients with ST-segment elevation myocardial infarction (STEMI) after primary percutaneous coronary intervention (PPCI). This study was an observational study. Two-hundred patients with STEMI living in Beijing, which is an average of 43.5 m above sea level (a low-altitude region), who underwent PPCI were enrolled (the control group). A further 200 patients with STEMI living in Xining, which is an average of 2,261 m above sea level (moderate-altitude region), who underwent PPCI were enrolled (the moderate-altitude group). NCL progression and related clinical factors were compared between the two groups. Results: The rate of NCL progression 12 months after PPCI in the moderate-altitude group was significantly lower compared with the control group (p < 0.01). There were 158 patients without NCL progression (group A) and 42 patients with NCL progression (group B) in the control group and 186 patients without NCL progression (group C) and 14 patients with NCL progression (group D) in the moderate-altitude group. Serum adrenaline and noradrenaline concentrations in group B were significantly higher compared with group A (p < 0.001), and serum adrenaline and noradrenaline concentrations in group D were significantly higher compared with group C (p < 0.001). Serum adrenaline, noradrenaline, and C-reactive protein concentrations in patients without NCL progression (n = 344) were significantly lower compared with patients with NCL progression (n = 56) (p < 0.01). Conclusions: Moderate altitude may prevent NCL progression. Moderate altitude may be useful for clinical rehabilitation in patients with STEMI after PPCI. [ABSTRACT FROM AUTHOR]

Liver ischemia–reperfusion (IR) injury is associated with poor outcome after liver transplantation and liver resections. Hexafluoroisopropanol (HFIP) is a tri‐fluorinated metabolites of volatile anesthetics and has modulatory effects on inflammation that have been observed mainly in cell culture experiments. In this survey, we investigated the effects of HFIP in a rat model of normothermic hepatic ischemia–reperfusion injury. Twenty‐four male Wistar rats were randomized into three groups: (1) control in which animals were submitted to 30 min of partial liver ischemia with resection of non‐ischemic liver lobes immediate after reperfusion, (2) pre‐ischemia (PI) group in which animals received intravenous HFIP (67 mg/kg) 5 min before liver ischemia, and (3) pre‐reperfusion (PR) group in which animals received intravenous HFIP (67 mg/kg) 5 min before reperfusion. Four hours after reperfusion, all animals were euthanized for sample collection. Aspartate and alanine transaminases, glucose, and high mobility group box‐1 (HMGB‐1) protein concentrations showed a significant decreased, and malondialdehyde was increased in the PR group compared with control and PI groups. Interleukin 6 (IL‐6) was increased in the PI group compared with control and PR groups. IL‐10 and ‐12 were increased in the PR and PI groups, respectively, when compared with the control group. Glucose decreased in the PR when compared with the control group. Post‐conditioning with HFIP led to a decrease in hepatocellular injury and was associated with a downregulation of HMGB‐1. The HFIP resulted in a better control of inflammatory response to ischemia–reperfusion even without causing a reduction in oxidative stress. [ABSTRACT FROM AUTHOR]

Background: Acute renal failure due to crush syndrome is one of the leading causes of death in disasters. Ischemic Postconditioning (IPC) is a potentially effective strategy to protect against ischemic reperfusion injury, but a few studies noted its protective effect in crush induced acute kidney injury (AKI). Hence, this study investigated the optimal IPC strategy to prevent crush induced AKI and reveal related cellular mechanisms. Methods: The right lower extremities of rabbits were constantly compressed for 8 h and then performed five cycles of clamping and releasing the femoral artery and vein before depression using a clip. In terms of the duration of clamping and releasing, the animals were randomly divided into 5 groups, Control, IPC-5sec, IPC-30sec, IPC-1min, and IPC-5min groups; 6 rabbits for each group. Biomarkers of inflammation, renal function, renal tubular injury, and muscular injury, apoptosis, and cellular senescence in kidney were detected. Results: Six hours after decompression, the levels of Serum Creatine (SCr), Blood Urea Nitrogen (BUN), K+, and Interleukin-6 (IL-6) in IPC-1min and IPC-5min groups were lower than Control, with a statistically significant difference. The morphological study of Periodic Acid-Schiff (PAS) staining demonstrated that 6 h after decompression, IPC-1min can attenuate renal tubular damage renal tubule. Meanwhile, the level of Neutrophil Gelatinase-Associated Lipocalin (NGAL) in circulation in the IPC-30sec, IPC-1min, and IPC-5min groups was significantly decreased compared with the Control group, 2 h after decompression. On the other hand, the levels of serum Creatine Kinase (CK) and Myoglobin (Mb), and the morphological change of muscular damage detected by hematoxylin and eosin (H&E) staining in IPC-1min-treated group were significantly lower than Control group 6 hours after decompression. Further results of the cellular mechanism showed that the apoptotic markers of Terminal deoxynucleotidyl Transferase-mediated dUTP Nick End Labeling (TUNEL) and Caspase3 and the cell senescent markers of senescence-associated β-galactosidase (SA-β-Gal) and nuclear LAMNB1 have changed significantly in the IPC-1min group, compared with the control group. Conclusions: Performing 5 cycles of 1-min IPC would be a convenient, time-saving, and effective method to prevent crush-induced AKI by attenuating the release of nephrotoxic substances after decompression and downregulation of the expression of apoptosis and cellular senescence biomarkers. [ABSTRACT FROM AUTHOR]

Heart transplantation is facing a shortage of grafts. Donation after Circulatory Death (DCD) would constitute a new potential of available organs. In the present work, we aimed to evaluate whether Postconditioning (ischemic or with ciclosporin-A (CsA)) could reduce ischemia-reperfusion injury in a cardiac arrest model when applied at the start of reperfusion or after a delay. An isolated rat heart model was used as a model of DCD. Hearts were submitted to a cardiac arrest of 40 min of global warm ischemia (37 °C) followed by 3 h of 4 °C-cold preservation, then 60 min reperfusion. Hearts were randomly allocated into the following groups: control, ischemic postconditioning (POST, consisting of two episodes each of 30 s ischemia and 30 s reperfusion at the onset of reperfusion), and CsA group (CsA was perfused at 250 nM for 10 min at reperfusion). In respective subgroups, POST and CsA were applied after a delay of 3, 10, and 20 min. Necrosis was lower in CsA and POST versus controls (p < 0.01) whereas heart functions were improved (p < 0.01). However, while the POST lost its efficacy if delayed beyond 3 min of reperfusion, CsA treatment surprisingly showed a reduction of necrosis even if applied after a delay of 3 and 10 min of reperfusion (p < 0.01). This cardioprotection by delayed CsA application correlated with better functional recovery and higher mitochondrial respiratory index. Furthermore, calcium overload necessary to induce mitochondrial permeability transition pore (MPTP) opening was similar in all cardioprotection groups, suggesting a crucial role of MPTP in this delayed protection of DCD hearts. [ABSTRACT FROM AUTHOR]

Ischemic preconditioning (IPC), and ischemic postconditioning (IPost) have a significant protective effect on myocardial ischemia/reperfusion (MI/R) injury by alleviating oxidative stress and mitochondrial disturbances, although the underlying molecular mechanisms are unclear. The study was to demonstrate that cardioprotection against anoxia/reoxygenation (A/R) injury is transduced via the Notch1/Hes1/VDAC1 signaling pathway. Using mass spectrometry and tandem affinity purification (TAP), to screen for differentially expressed proteins associated with Hes1, followed by standard bioinformatics analysis. The co‐immunoprecipitation (Co‐IP) assay confirmed an interaction between Hes1 and VDAC1 proteins. H9c2 cells were transfected with Hes1 adenoviral N‐terminal TAP vector (AD‐NTAP/Hes1) and Hes1‐short hairpin RNA adenoviral vector (AD‐Hes1‐shRNA) to establish A/R injury, IPC, and IPost models, respectively. The expression of Hes1 and VDAC1 proteins were measured by western blot analysis, while the levels of reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), and apoptosis were evaluated by flow cytometry. AD‐NTAP/Hes1 can activate the exogenous protein expression of Hes1, thus decreasing creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) activity and promoting cell viability. The study found that VDAC1 was a potential target protein for Hes1 and the overexpression of Hes1 protein expression downregulated protein expression levels of VDAC1, reduced ROS production, stabilized ΔΨm, and inhibited apoptosis in H9c2 cells. Additionally, downregulation of Hes1 protein expression also upregulated VDAC1 protein expression, increased ROS production, imbalanced ΔΨm, promoted cell apoptosis, and attenuated the cardioprotection afforded by IPC and IPost. The Notch1/Hes1 signaling pathway activated by IPC/IPost can directly downregulate the protein expression of VDAC1 and consequently relieve A/R injury. [ABSTRACT FROM AUTHOR]

MicroRNAs, contained in exosomes or freely circulating in the plasma, might play a pivotal role in the infarct-sparing effect exerted by remote limb ischemic postconditioning (RLIP). The aims of the present study were: (1) To evaluate the effect of pure exosomes isolated from plasma of animals subjected to RLIP systemically administered to ischemic rats; (2) To finely dissect exosomes content in terms of miRNAs; (3) To select those regulatory miRNAs specifically expressed in protective exosomes and to identify molecular pathways involved in their neurobeneficial effects. Circulating exosomes were isolated from blood of animals exposed to RLIP and administered to animals exposed to tMCAO by intracerebroventricular, intraperitoneal or intranasal routes. Exosomal miRNA signature was evaluated by microarray and FISH analysis. Plasmatic exosomes isolated from plasma of RLIP rats attenuated cerebral ischemia reperfusion injury and improved neurological functions until 3 days after ischemia induction. Interestingly, miR-702-3p and miR-423-5p seem to be mainly involved in exosome protective action by modulating NOD1 and NLRP3, two key triggers of neuroinflammation and neuronal death. Collectively, the results of the present work demonstrated that plasma-released exosomes after RLIP may transfer a neuroprotective signal to the brain of ischemic animals, thus representing a potentially translatable therapeutic strategy in stroke. [ABSTRACT FROM AUTHOR]

Limb remote ischemic postconditioning (LRIP) and paeoniflorin (PF) both can ameliorate cerebral ischemia reperfusion (I/R) injury. At present, whether LRIP combined with PF can achieve better therapeutic effect is unknown. This study explored the alleviating effect and mechanism of LRIP in combination with PF on cerebral I/R injury in rats. Middle cerebral artery occlusion (MCAO) surgery was performed on rats except Sham group. Then PF (2.5 mg/kg, 5 mg/kg, 10 mg/kg) was administrated by intraperitoneal injection 10 min before the start of reperfusion. LRIP was operated on the left femoral artery at 0 h of reperfusion. Behavioral testing was used to assess neurological impairment, while TTC staining was used to examine infarct volume. Protein expression of MyD88, TRAF6, p38-MAPK and phosphorylation of p47phox in neutrophils from rat peripheral blood were tested by Western blot. Rat bone marrow neutrophils were extracted and incubated for 24 h with serum from rats after LRIP combined with PF. p38 MAPK inhibitor group was administrated SB203580 while the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor group was administrated Apocynin. Neutrophils were stimulated by fMLP (10 μM). Reactive oxygen species (ROS) production and protein expression of MyD88, TRAF6, p38 MAPK, and p47phox (ser 304 and ser 345) were detected. LRIP combined with PF (5 mg/kg) reduced cerebral infarct volume, ameliorated neurological deficit score (NDS), decreased fMLP-stimulated ROS release and downregulated the protein expression of MyD88, TRAF6, p38-MAPK and phosphorylation of p47phox (ser 304 and ser 345) in neutrophils. The protective effect of LRIP combined with PF on cerebral I/R injury was better than either alone. Taken together, we provided solid evidence to demonstrate that the combination of LRIP and PF had potential to alleviate cerebral I/R injury, which was regulated by MyD88-TRAF6-p38 MAPK pathway and neutrophil NADPH oxidase pathway. [Display omitted] • The protective effect of LRIP combined with PF on cerebral I/R injury is better than either alone. • LRIP combined with PF downregulate MyD88/TRAF6/p38-MAPK pathway in rat peripheral blood neutrophils. • In vitro , LRIP combined with PF serum downregulate MyD88/TRAF6/p38-MAPK pathway in bone marrow neutrophils. [ABSTRACT FROM AUTHOR]

Background: Diabetes decreased cardioprotective potential of ischemic postconditioning (IPOC), atrial natriuretic peptide (ANP) induced the cardioprotection against ischemic-reperfusion (I/R) injury. The present study has been designed to investigate the role of ANP induced postconditioning in diabetic rat heart. Methods: Isolated Langendorff perfused normal and diabetic rat hearts were stabilized for 10 min proceed by global ischemia further followed by four cycles of IPOC, each cycle comprised 5 min of reperfusion and 5 min of ischemia at onset of 120 min of reperfusion. Perfusion of ANP (0.1μM/l) with Krebs–Henseleit Buffer solution in isolated diabetic rat heart for four-cycle of IPOC significantly decreased I/R-induced myocardial infarct size and release of CK-MB and lactate dehydrogenase (LDH) level in coronary effluent. Results: Four cycles of IPOC-induced cardioprotection noted by decreased in infarct size and also in release of LDH and CK-MB in normal rat heart. However, IPOC-induced cardioprotection was completely attenuated in isolated heart obtained from diabetic rat. Perfusion of ANP (0.1μM/L) significantly restored the attenuated cardioprotection in diabetic rat heart, which was completely blocked by perfusion of L-NAME (100μM/L), an eNOS inhibitor. Conclusion: So that, ANP restored cardioprotective affect in diabetic rat heart, which was completely abolished by the perfusion of L-NAME (100μM/L), an eNOS inhibitor.

During acute reperfusion, the expression profiles of long noncoding RNAs in adult rats with focal cerebral ischemia undergo broad changes. However, whether long noncoding RNAs are involved in neuroprotective effects following focal ischemic stroke in rats remains unclear. In this study, RNA isolation and library preparation was performed for long noncoding RNA sequencing, followed by determining the coding potential of identified long noncoding RNAs and target gene prediction. Differential expression analysis, long noncoding RNA functional enrichment analysis, and co-expression network analysis were performed comparing ischemic rats with and without ischemic postconditioning rats. Rats were subjected to ischemic postconditioning via the brief and repeated occlusion of the middle cerebral artery or femoral artery. Quantitative real-time reverse transcription-polymerase chain reaction was used to detect the expression levels of differentially expressed long noncoding RNAs after ischemic postconditioning in a rat model of ischemic stroke. The results showed that ischemic postconditioning greatly affected the expression profile of long noncoding RNAs and mRNAs in the brains of rats that underwent ischemic stroke. The predicted target genes of some of the identified long noncoding RNAs (cis targets) were related to the cellular response to ischemia and stress, cytokine signal transduction, inflammation, and apoptosis signal transduction pathways. In addition, 15 significantly differentially expressed long noncoding RNAs were identified in the brains of rats subjected to ischemic postconditioning. Nine candidate long noncoding RNAs that may be related to ischemic postconditioning were identified by a long noncoding RNA expression profile and long noncoding RNA-mRNA co-expression network analysis. Expression levels were verified by quantitative real-time reverse transcription-polymerase chain reaction. These results suggested that the identified long noncoding RNAs may be involved in the neuroprotective effects associated with ischemic postconditioning following ischemic stroke. The experimental animal procedures were approved by the Animal Experiment Ethics Committee of Kunming Medical University (approval No. KMMU2018018) in January 2018.

Abstract Liver ischemia–reperfusion (IR) injury is associated with poor outcome after liver transplantation and liver resections. Hexafluoroisopropanol (HFIP) is a tri‐fluorinated metabolites of volatile anesthetics and has modulatory effects on inflammation that have been observed mainly in cell culture experiments. In this survey, we investigated the effects of HFIP in a rat model of normothermic hepatic ischemia–reperfusion injury. Twenty‐four male Wistar rats were randomized into three groups: (1) control in which animals were submitted to 30 min of partial liver ischemia with resection of non‐ischemic liver lobes immediate after reperfusion, (2) pre‐ischemia (PI) group in which animals received intravenous HFIP (67 mg/kg) 5 min before liver ischemia, and (3) pre‐reperfusion (PR) group in which animals received intravenous HFIP (67 mg/kg) 5 min before reperfusion. Four hours after reperfusion, all animals were euthanized for sample collection. Aspartate and alanine transaminases, glucose, and high mobility group box‐1 (HMGB‐1) protein concentrations showed a significant decreased, and malondialdehyde was increased in the PR group compared with control and PI groups. Interleukin 6 (IL‐6) was increased in the PI group compared with control and PR groups. IL‐10 and ‐12 were increased in the PR and PI groups, respectively, when compared with the control group. Glucose decreased in the PR when compared with the control group. Post‐conditioning with HFIP led to a decrease in hepatocellular injury and was associated with a downregulation of HMGB‐1. The HFIP resulted in a better control of inflammatory response to ischemia–reperfusion even without causing a reduction in oxidative stress.

Objectives: To systematically review studies using remote ischemia postconditioning (RIPostC) for ischemic stroke in experimental models and obtain factors that significantly influence treatment outcomes. Materials and Methods: Peer‐reviewed studies were identified and selected based on the eligibility criteria, followed by extraction of data on potentially influential factors related to model preparation, postconditioning, and measure time based on outcome measures including infarct size, neurological scales, and cell tests with autophagy, apoptosis, normal‐neuron, and damaged‐neuron counting. Then, all data were preprocessed, grouped, and meta‐analyzed with the indicator of the standardized mean difference. Results: Fifty‐seven studies with 224 experiments (91 for infarct size, 92 for neurological scales, and 41 for cell‐level tests) were included. There was little statistical difference between different model preparations, treated body parts, number of treatments, and sides. And treatment effect was generally a positive correlation with the duration of conditioning time to stroke onset with exceptions at some time points. Based on infarct size, the number of cycles per treatment, duration of occlusion, and release per cycle showed significant differences. Combined with the effect sizes by other measures, the occlusion/release duration of 8–10 min per cycle is better than 5 min, and three cycles per treatment were most frequently used with good effects. Effect also varied when measuring at different times, showing statistical differences in infarct size and most neurological scales. RIPostC is confirmed as an effective therapeutic intervention for ischemic stroke, while the RIPostC‐mediated autophagy level being activated or inhibited remained conflicting. Conclusions: Conditioning time, number of cycles per treatment, duration of occlusion, and release per cycle were found to influence the treatment effects of RIPostC significantly. More studies on the relevant influential factors and autophagy mechanisms are warranted. [ABSTRACT FROM AUTHOR]

Background: There is evidence that remote limb ischemic postconditioning (RIPostC) can reduce ischemia-reperfusion injury (IRI) and improve the prognosis of patients with ischemic stroke. However, so far, only few relevant clinical studies have been conducted. Therefore, we carried out a meta-analysis of eligible randomized controlled trials to compare the RIPostC group with a control group (no intervention or sham surgery) in patients with ischemic stroke. Methods: Four English-language publication databases, PubMed, Cochrane, Embase, and Web of Science, were systematically searched up to March 2022. The data were analyzed using Review Manager fixed-effects and random-effects models. Results: A total of 12 studies were included, and 11 of those were analyzed quantitatively. Compared to controls, The RIPostC group showed significantly reduced NIHHS scores in patients with ischemic stroke, (MD: -1.09, 95% confidence interval [CI]: -1.60, -0.57, P < 0.0001) and improved patients' Montreal Cognitive Assessment (MoCA) scores, (MD: 1.89, 95% CI: 0.78, 3.00, P = 0.0009), Our results showed that RIPostC is safe, (RR = 0.81, 95%CI: 0.61, 1.08, P = 0.15). Conclusion: Our meta-analysis showed that RIPostC is safe and effective and has a positive cerebral protective effect in patients with ischemic stroke, which is safe and effective, and future large-sample, multicenter trials are needed to validate the cerebral protective effect of RIPostC. [ABSTRACT FROM AUTHOR]