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Stroke remains one of the major health challenges due to its high rates of mortality and long-term disability, necessitating the development of effective therapeutic treatment. This study aims to explore the neuroprotective effects of hypoxic postconditioning (HPC) using a cell-based 3D cortical ischemic-hypoxic injury model. Our model employs murine cells to investigate HPC-induced modulation of glial cell reactivity and intercommunication post-oxygen-glucose deprivation-reoxygenation (OGD-R) injury. We found that a single HPC session (1HPC) provided the most significant neuroprotection post-OGD-R compared to multiple intermittent hypoxic treatments, evidenced by improved spheroidal structure, enhanced cell survival and reduced apoptosis, optimal modulation of neuronal phenotypes, dampened ischemic responses, and augmented neurite outgrowth of spheroids. Furthermore, 1HPC suppressed both pro-inflammatory A1 and anti-inflammatory A2 astrocyte phenotypes despite the induction of astrocyte activation while reducing microglial activation with inhibited M1 and M2 reactive states. This was accompanied by a decrease in gene expression of the pro-inflammatory cytokines essential to microglia-astrocyte signaling, collectively suggesting a shift of glial cells away from their traditional reactive states for neuroprotection. This study highlights the potential of 1HPC as a novel therapeutic intervention for ischemic injury via the modulation of neuroprotective glial reactivity. Moreover, the 3D cortical ischemic-hypoxic injury model employed here holds enormous potential serving as a disease model to further elucidate the underlying mechanism of HPC, which can also extend to the applications in brain regeneration, drug development, and the modeling of neural diseases., (© 2024. The Author(s).)

Background/aim: Acute lung injury (ALI) is a syndrome characterized by the disruption of alveolar endothelial and epithelial barriers, neutrophilic infiltration in pulmonary regions, and non-cardiogenic edema, associated with high mortality and morbidity. Despite intensive research efforts, there is currently no approved specific treatment for the condition. The aim of this study was to investigate the potential beneficial effect of ischemic post-conditioning in lipopolysaccharide (LPS)-induced lung injury and its possible association with inflammatory and apoptotic processes., Materials and Methods: Lung injury was induced in rats by a single intraperitoneal administration of 10 mg/kg LPS. Under anesthesia, latex tourniquets were wrapped around both hind limbs of the animals in a region close to the body to achieve complete ischemia. The ischemic conditioning procedure consisted of four cycles of 10 min of ischemia followed by 10 min of reperfusion. Inflammation, and apoptosis levels were measured using ELISA. Hematoxylin and eosin staining was used for histopathological evaluation, while TUNEL staining was employed for apoptotic cell counting. One-way analysis of variance (ANOVA) with post hoc Tukey test was used for comparisons between groups., Results: Intraperitoneal LPS administration induced neutrophil infiltration and apoptotic cell death in lung tissue. These effects were prevented by remote ischemic postconditioning (RIPostC) application. Additionally, the beneficial effects of ischemic conditioning can be transferred via serum., Conclusion: RIPostC can ameliorate LPS-induced ALI. The mechanism of the protective effects of RIPostC may lie in the suppression of apoptosis and neutrophil infiltration., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Subarachnoid hemorrhage (SAH) is associated with neurocognitive impairment. Recent data suggest that sevoflurane attenuates edema formation after SAH in rats. However, so far, no information is available about the long-term repair phase, nor if sevoflurane impacts functionality by increasing vascularity. This study tested whether sevoflurane postconditioning would improve long-term neurologic deficit through increased formation of new vessels close to the hemorrhage area., Methods: Fifty-three animals were subjected to SAH or sham surgery with or without a 2-hour sevoflurane postconditioning (versus propofol anesthesia). Animal survival, including dropout animals due to death or reaching termination criteria, as well as neurologic deficit, defined by the Garcia score, were assessed 2 hours after recovery until postoperative day 14. On day 14, blood samples and brain tissue were harvested. Vessel density was determined by the number of cluster of differentiation 31 (CD31)-positive vessels, and activated glial cells by glial fibrillary acidic protein (GFAP)-positive astrocytes per field of view., Results: The survival rate for sham animals was 100%, 69% in the SAH-propofol and 92% in the SAH-sevoflurane groups. According to the log-rank Mantel-Cox test, survival curves were significantly different ( P = .024). The short-term neurologic deficit was higher in SAH-propofol versus SAH-sevoflurane animals 2 hours after recovery and on postoperative day 1 (propofol versus sevoflurane: 14. 6 ± 3.4 vs 15. 9 ± 2.7 points, P = .034, and 16. 2 ± 3.5 vs 17. 8 ± 0.9 points, P = .015). Overall complete recovery from neurologic deficit was observed on day 7 in both SAH groups (18. 0 ± 0.0 vs 18. 0 ± 0.0 points, P = 1.000). Cortical vascular density increased to 80. 6 ± 15.0 vessels per field of view in SAH-propofol animals (vs 71. 4 ± 10.1 in SAH-sevoflurane, P < .001). Activation of glial cells, an indicator of neuroinflammation, was assessed by GFAP-positive astrocytes GFAP per field of view. Hippocampal GFAP-positive cells were 201 ± 68 vs 179 ± 84 cells per field of view in SAH-propofol versus SAH-sevoflurane animals ( P < .001)., Conclusions: Sevoflurane postconditioning improves survival by 23% (SAH-sevoflurane versus SAH-propofol). The sevoflurane intervention could attenuate the early neurologic deficit, while the long-term outcome was similar across the groups. A higher vascular density close to the SAH area in the propofol group was not associated with improved outcomes., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2024 International Anesthesia Research Society.)

Introduction: In recent years, a number of studies have demonstrated that hypoxia reoxygenation (HR) induced by ischemia postconditioning (IPC) reduces endothelial barrier dysfunction and inflammation in various models. When HR occurs, the P38 mitogen-activated protein kinase (P38 MAPK) breaks down the endothelial barrier. But no study has clearly clarified the effect of hypoxia postconditioning (HPC) on P38 MAPK in human dermal microvascular endothelial cells. Therefore, we investigated the function of HPC on P38 MAPK during HR in vitro., Methods: Human dermal microvascular endothelial cells were cultured in a hypoxic incubator for 8 h. Then cells were reperfused for 12 h (reoxygenation) or postconditioned by 5 min of reoxygenation and 5 min of re-hypoxia 3 times followed by 11.5 h reoxygenation. SB203580 was used as an inhibitor of P38 MAPK. Cell counting kit-8 assay kits were employed to detect cell activity. The corresponding levels of IL-6, IL-8 and IL-1β were examined via Enzyme-Linked ImmunoSorbent Assay. The endothelial barrier was evaluated using fluorescein isothiocyanate-dextran leakage assay. Western blot was used to detect claudin-5, phosphorylation of P38 MAPK (P-P38 MAPK) and P38 MAPK expression. Claudin-5 localization was studied by immunofluorescence., Results: HR induced endothelial barrier hyperpermeability, elevated inflammation levels, and increased the P-P38 MAPK. But HPC reduced cell injury and maintained the integrity of the endothelial barrier while inhibiting P-P38 MAPK and increasing expression of claudin-5. HPC redistributed claudin-5 in a continuous and linear pattern on the cell membrane., Conclusions: HPC protects against HR induced downregulation and redistribution of claudin-5 by inhibiting P-P38 MAPK., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Remote ischemic post-conditioning (RIPostC) can reduce cerebral ischemia reperfusion injury (IRI) by inducing endogenous protective effects, the distal limb ischemia post-treatment and in situ ischemia post-treatment were classified according to the site of intervention. And in the process of clinical application distal limb ischemia post-treatment is more widely used and more conducive to clinical translation. Therefore, in this paper, we review the mechanism of action and clinical application of RIPostC in cerebral ischemia, hoping to provide reference help for future experimental directions and clinical translation., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

To assess the effectiveness and molecular mechanisms of mild hypothermia and remote ischemic postconditioning (RIPC) in patients with acute ischemic stroke (AIS) who have undergone thrombolysis therapy. A total of 58 AIS patients who received recombinant tissue plasmin activator (rt-PA) intravenous thrombolysis were included in this prospective study. Participants were randomly allocated to the experimental group (rt-PA intravenous thrombolysis plus mild hypothermic ice cap plus remote ischemic brain protection, n  = 30) and the control group (rt-PA intravenous thrombolysis plus 0.9% saline, n  = 28). The RIPC was performed for 14 consecutive days on both upper limb arteries spaced 2 minutes apart. Five cycles of ischemia-reperfusion were performed sequentially (2-2, 3-3, 4-4, 5-5, 5-0 minutes, respectively). The outcome measures of the National Institute of Health stroke scale (NIHSS) score, volume of cerebral infarction, serum levels of superoxide dismutase (SOD), malondialdehyde (MDA), interleukin-1β, tumor necrosis factor α, nuclear factors kappa B (NF-κB), and NOD-1ike receptor pyrin 3 (NLRP3) were evaluated at different time points after treatment. Similarly, the 90-day modified Rankin Scale (mRS) scores were compared between the two groups. After treatment, the NIHSS score, MDA, NF-κB, and NLRP3 levels in the experimental group were significantly lower than those in the control group ( p  < 0.05). While the SOD in the experimental group was significantly higher than in the control group ( p  < 0.05), the NIHSS scores decreased within groups (all p  < 0.05) in both experimental and control groups. The 90-day mRS score (0-2 points) in the experimental group was significantly higher than that in the control group (73.33% vs. 53.57%, p  < 0.05) and no significant differences were observed in the safety indices between the two groups (all p  > 0.05). Our study shows that combining mild hypothermia and RIPC has a positive effect on brain protection and can significantly reduce the oxidative stress and associated outburst of inflammatory response. The Clinical Trial Registration number is ChiCTR2300073136.

Brain-derived estrogen (BDE2) is gaining attention as an endogenous neurotransmitter. Recent research has revealed that selectively removing the aromatase gene, the pivotal enzyme responsible for BDE2 synthesis, in forebrain neurons or astrocytes can lead to synaptic loss and cognitive impairment. It is worth noting that remote ischemia post-conditioning (RIP), a non-invasive technique, has been shown to activate natural protective mechanisms against severe ischemic events. The aim of our study was to investigate whether RIP triggers aromatase-BDE2 signaling, shedding light on its neuroprotective mechanisms after global cerebral ischemia (GCI) in ovariectomized rats. Our findings are as follows: (1) RIP was effective in mitigating ischemic damage in hippocampal CA1 neurons and improved cognitive function after GCI. This was partially due to increased Aro-BDE2 signaling in CA1 neurons. (2) RIP intervention efficiently enhanced pro-survival kinase pathways, such as AKT, ERK1/2, CREB, and suppressed CaMKIIα signaling in CA1 astrocytes induced by GCI. Remarkably, inhibiting CaMKIIα activity led to elevated Aro-BDE2 levels and replicated the benefits of RIP. (3) We also identified the positive mediation of Cav1.2, an LVGCC calcium channel, on CaMKIIα-Aro/BDE2 pathway response to RIP intervention. (4) Significantly, either RIP or CaMKIIα inhibition was found to alleviate reactive astrogliosis, which was accompanied by increased pro-survival A2-astrocyte protein S100A10 and decreased pro-death A1-astrocyte marker C3 levels. In summary, our study provides compelling evidence that Aro-BDE2 signaling is a critical target for the reparative effects of RIP following ischemic insult. This effect may be mediated through the CaV1.2-CaMKIIα signaling pathway, in collaboration with astrocyte-neuron interactions, thereby maintaining calcium homeostasis in the neuronal microenvironment and reducing neuronal damage after ischemia., (© 2024. The Author(s).)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

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., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: 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., Purpose: This study explored the alleviating effect and mechanism of LRIP in combination with PF on cerebral I/R injury in rats., Methods: 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 p47 phox 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 p47 phox (ser 304 and ser 345) were detected., Results: 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 p47 phox (ser 304 and ser 345) in neutrophils., Conclusion: 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

Neuronal death resulting from ischemic stroke is the primary cause of adult mortality and disability, and effective neuroprotective agents for poststroke intervention are still lacking. Remote ischemic postconditioning (RIPostC) has demonstrated significant protective effects against ischemia in various organs; however, the specific mechanisms are not fully understood. This study investigated the potential neuroprotective mechanisms of RIPostC in the context of ischemic stroke. Using a rat model of middle cerebral artery occlusion, we found that RIPostC mitigated neurological damage, improved movement in the open-field test, and protected against neuronal apoptosis. In terms of energy metabolism, RIPostC enhanced ATP levels, suppressed lactate content, and increased the production of ketone bodies (KBs). In the ferroptosis assay, RIPostC protected against lipoperoxidation, reversed the reduction of glutathione peroxidase 4 (GPX4), and mitigated the excessive expression of long-chain acyl-CoA synthetase family member 4 (ACSL4). In oxygen-glucose deprivation/reoxygenation-treated HT22 cells, KBs maintained GPX4 levels, suppressed ACSL4 expression, and preserved the mitochondrial cristae number. However, the effect of KBs on the expression of GPX4, ACSL4, and the number of mitochondrial cristae was blocked by erastin. Moreover, both RIPostC and KBs reduced total iron and ferrous ion content by repressing iron transporters both in vitro and in vivo . In conclusion, KBs-induced mitigation of ferroptosis could represent a new therapeutic mechanism for RIPostC in treating stroke.

Sevoflurane postconditioning has been shown to provide neuroprotection against cerebral hypoxia-ischemia injury, but the mechanisms remain elusive. Microtubule-associated protein 2 (MAP2) is implicated in early neuronal hypoxia-ischemia injury. This study aimed to investigate whether the neuroprotective effects of sevoflurane postconditioning are related to the Akt/GSK-3β pathway and its downstream target MAP2 in zebrafish hypoxia/reoxygenation (H/R) model. Sevoflurane postconditioning or GSK-3β inhibitor TDZD-8 were used to treat H/R zebrafish. The cerebral infarction, neuronal apoptosis, and mitochondrial changes were evaluated using TTC staining, TUNEL staining, and transmission electron microscopy, respectively. The distribution of MAP2 in the brain was determined by immunofluorescence imaging. The levels of Akt, p-Akt, GSK-3β, p-GSK-3β, and MAP2 proteins were evaluated by Western blotting. The neurobehavioral recovery of zebrafish was assessed based on optokinetic response behavior. Our results indicated that sevoflurane postconditioning and TDZD-8 significantly reduced the cerebral infarction area, suppressed cell apoptosis, and improved mitochondrial integrity in zebrafish subjected to H/R. Furthermore, sevoflurane postconditioning and TDZD-8 elevated the ratios of p-Akt/Akt and p-GSK-3β/GSK-3β. However, the neuroprotective effect of sevoflurane postconditioning was effectively abolished upon suppression of MAP2 expression. In conclusion, sevoflurane postconditioning ameliorated cerebral H/R injury and facilitated the restoration of neurobehavioral function through the activation of Akt/GSK-3β pathway and promotion of MAP2 expression., Competing Interests: Declaration of Competing Interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work in this paper. There is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Acidic postconditioning by transient CO 2 inhalation applied within minutes after reperfusion has neuroprotective effects in the acute phase of stroke. However, the effects of delayed chronic acidic postconditioning (DCAPC) initiated during the subacute phase of stroke or other acute brain injuries are unknown. Mice received daily DCAPC by inhaling 5%/10%/20% CO 2 for various durations (three cycles of 10- or 20-min CO 2 inhalation/10-min break) at days 3-7, 7-21, or 3-21 after photothrombotic stroke. Grid-walk, cylinder, and gait tests were used to assess motor function. DCAPC with all CO 2 concentrations significantly promoted motor functional recovery, even when DCAPC was delayed for 3-7 days. DCAPC enhanced the puncta density of GAP-43 (a marker of axon growth and regeneration) and synaptophysin (a marker of synaptogenesis) and reduced the amoeboid microglia number, glial scar thickness and mRNA expression of CD16 and CD32 (markers of proinflammatory M1 microglia) compared with those of the stroke group. Cerebral blood flow (CBF) increased in response to DCAPC. Furthermore, the mRNA expression of TDAG8 (a proton-activated G-protein-coupled receptor) was increased during the subacute phase of stroke, while DCAPC effects were blocked by systemic knockout of TDAG8, except for those on CBF. DCAPC reproduced the benefits by re-expressing TDAG8 in the peri-infarct cortex of TDAG8-/- mice infected with HBAAV2/9-CMV-TDAG8-3flag-ZsGreen. Taken together, we first showed that DCAPC promoted functional recovery and brain tissue repair after stroke with a wide therapeutic time window of at least 7 days after stroke. Brain-derived TDAG8 is a direct target of DCAPC that induces neuroreparative effects., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The effectiveness of ischemic postconditioning (iPoC) in patients with ST-elevation myocardial infarction (STEMI) without ischemic preconditioning has not been determined. Therefore, we investigated the impact of iPoC and its potential mechanism related to heat shock protein 72 (HSP72) induction on myocardial salvage in patients with STEMI without prodromal angina (PA).We retrospectively analyzed data from 102 patients with STEMI with successful reperfusion among 323 consecutive patients with acute coronary syndrome. Among these, 55 patients with iPoC (iPoC (+) ) underwent 4 cycles of 60-second inflation and 30-second deflation of the angioplasty balloon. Both the iPoC (+) and iPoC (-) groups were divided into 2 further subgroups: patients with PA (PA (+) ) and those without (PA (-) ). We analyzed HSP72 levels in neutrophils, which were measured until 48 hours after reperfusion. I-123 β-methyl-p-iodophenyl-pentadecanoic acid (BMIPP) scintigraphy was performed within a week of reperfusion therapy. In 64% of patients, thallium-201 (TL) scintigraphy was performed 6-8 months after STEMI onset.Using BMIPP and TL, in the PA (-) subgroups, the iPoC (+) group had a significantly greater myocardial salvage ratio than the iPoC (-) group. iPoC was identified as an independent predictor of the myocardial salvage ratio. The HSP72 increase ratio was significantly elevated in the iPoC (+) PA (-) group. Importantly, the myocardial salvage effect in patients without PA was significantly correlated with the HSP72 increase ratio, which was greater in patients with iPoC.These results suggest the potential impact of iPoC via HSP72 induction on myocardial salvage; however, the effects may be limited to patients with STEMI without PA.

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., (© 2024. The Author(s).)

Patients with acute ischemic stroke achieve inadequate benefit due to the short therapeutic window for thrombolysis and the risk of ischemia/reperfusion (IR) injury. Ischemic postconditioning induces endogenous cerebral protection for acute ischemic stroke, although the protective mechanisms associated with ischemic postconditioning haven't been well clarified. In present study, the rat models of ischemic cerebral stroke with in situ and remote ischemic postconditioning (ISP and RIP) were established successfully. The Zea Longa and the modified neurological severity scoring (mNSS) were carried out to evaluate neurological function in the rats, while the open field test was explored to estimate their autonomic athletic ability. The 2,3,5-riphenyltetrazolium chloride (TTC) staining method was used to measure the size of the infarcts. TUNEL and Nissl's staining were used to detect the apoptosis rate of cells in the ischemic penumbra, with the expression of TGFβ1, Smad2, and Smad3 in the ischemic penumbra and serum detected by immunohistochemical staining, qRT-PCR, Western blots, and ELISA analysis. We showed that application of both types of ischemic postconditioning had cerebral protective effects for the ischemic stroke rats, that included effective reduction in the volume of cerebral infarction, alleviation of apoptosis and inflammation in the ischemic penumbra, and promotion of recovery of neurological function. These effects included significantly enriched gene ontology (GO) terms after RIP intervention that were related to TGFβ1, increased protein levels of TGFβ1 and decreased levels of p-Smad2/3 and smad3 following RIP intervention. We showed that the TGFβ1-Smad2/3 signaling pathway was associated with the cerebral protection of ischemic postconditioning., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

This work evaluated the combined effects of alpha-lipoic acid (ALA) and ischemic postconditioning (Post) on myocardial infarction and cell death in rats with chronic type-II diabetes following ischemia/reperfusion injury. The rats received a high-fat diet and were given one intraperitoneal injection of 35 mg/kg streptozotocin to induce chronic diabetes. They were then pretreated with ALA (100 mg/kg/day, orally) for 5 weeks before undergoing ischemia/reperfusion (I/R) insult. The hearts experienced 35 min regional ischemia through ligating the left anterior descending coronary artery, followed by 60 min reperfusion. The Post protocol involved 6 cycles of a 10/10 s algorithm, applied during the early stage of reperfusion. The use of Post alone did not significantly alter lactate dehydrogenase and infarct size levels, while ALA showed positive effects. Similar findings were observed for apoptotic changes with single treatments. However, the concurrent administration of ALA and Post significantly reduced the protein expressions of Bax, Bax/Bcl2, and cleaved caspase-3 while increasing Bcl2 expression. Additionally, the histopathological findings of the combined therapy were superior to those of single treatments. The concomitant use of ALA and Post effectively inhibited apoptosis, leading to cardiac recovery after I/R injury in diabetic conditions. This strategy could improve outcomes for preserving diabetic hearts following I/R insults., Competing Interests: All author(s) undertook the responsibility of this study with no conflict of interests.

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., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.

Ischemic postconditioning (IPoC) is a technique suggested to reduce reperfusion injury in patients suffering acute ST-elevation myocardial infarction (STEMI), although its use is highly controversial. This meta-analysis aimed to evaluate the effect of IPoC with percutaneous coronary intervention in patients with acute STEMI, as measured by follow-up left ventricular ejection fraction (LVEF) on cardiac magnetic resonance imaging. The investigators searched PubMed, Embase, and Web of Science for all randomized controlled trials published during the last 2 decades. After the removal of duplicates, 2,021 articles from online databases had been identified using relevant search criteria. The included randomized controlled trials had studied patients with acute STEMI and Thrombolysis in Myocardial Infarction flow 0 to 1 at presentation and had measured follow-up LVEF using cardiac magnetic resonance imaging. Overall, 11 studies (n = 1,339 patients) qualified for inclusion. In each study, the control group did not differ significantly from the experimental group. The pooled data from included studies were analyzed using standardized mean difference between IPoC and control groups, and the 95% confidence interval for LVEF; the results were visualized using a forest plot. Bivariate regression analyses and 1-way analyses of LVEF coefficient ratios were done to isolate for various clinical and procedural parameters. An analysis of pooled data of the IPoC (n = 674) and control (n = 665) groups showed that IPoC did not significantly impact follow-up LVEF (using standardized mean difference 0.10, 95% confidence interval 0.00 to 0.21). Further analysis showed that IPoC did not improve follow-up LVEF when isolating for relevant clinical and procedural parameters. In conclusion, the use of IPoC as an adjunctive therapy to percutaneous coronary intervention seemingly provides no benefit to left ventricular systolic function, as quantified with cardiac magnetic resonance imaging, in patients with acute STEMI with Thrombolysis in Myocardial Infarction flow 0 to 1., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Importance: Despite some promising preclinical and clinical data, it remains uncertain whether remote ischemic conditioning (RIC) with transient cycles of limb ischemia and reperfusion is an effective treatment for acute stroke., Objective: To evaluate the effect of RIC when initiated in the prehospital setting and continued in the hospital on functional outcome in patients with acute stroke., Design, Setting, and Participants: This was a randomized clinical trial conducted at 4 stroke centers in Denmark that included 1500 patients with prehospital stroke symptoms for less than 4 hours (enrolled March 16, 2018, to November 11, 2022; final follow-up, February 3, 2023)., Intervention: The intervention was delivered using an inflatable cuff on 1 upper extremity (RIC cuff pressure, ≤200 mm Hg [n = 749] and sham cuff pressure, 20 mm Hg [n = 751]). Each treatment application consisted of 5 cycles of 5 minutes of cuff inflation followed by 5 minutes of cuff deflation. Treatment was started in the ambulance and repeated at least once in the hospital and then twice daily for 7 days among a subset of participants., Main Outcomes and Measures: The primary end point was improvement in functional outcome measured as a shift across the modified Rankin Scale (mRS) score (range, 0 [no symptoms] to 6 [death]) at 90 days in the target population with a final diagnosis of ischemic or hemorrhagic stroke., Results: Among 1500 patients who were randomized (median age, 71 years; 591 women [41%]), 1433 (96%) completed the trial. Of these, 149 patients (10%) were diagnosed with transient ischemic attack and 382 (27%) with a stroke mimic. In the remaining 902 patients with a target diagnosis of stroke (737 [82%] with ischemic stroke and 165 [18%] with intracerebral hemorrhage), 436 underwent RIC and 466 sham treatment. The median mRS score at 90 days was 2 (IQR, 1-3) in the RIC group and 1 (IQR, 1-3) in the sham group. RIC treatment was not significantly associated with improved functional outcome at 90 days (odds ratio [OR], 0.95; 95% CI, 0.75 to 1.20, P = .67; absolute difference in median mRS score, -1; -1.7 to -0.25). In all randomized patients, there were no significant differences in the number of serious adverse events: 169 patients (23.7%) in the RIC group with 1 or more serious adverse events vs 175 patients (24.3%) in the sham group (OR, 0.97; 95% CI, 0.85 to 1.11; P = .68). Upper extremity pain during treatment and/or skin petechia occurred in 54 (7.2%) in the RIC group and 11 (1.5%) in the sham group., Conclusions and Relevance: RIC initiated in the prehospital setting and continued in the hospital did not significantly improve functional outcome at 90 days in patients with acute stroke., Trial Registration: ClinicalTrials.gov Identifier: NCT03481777.

Remote ischemic conditioning (RIC) has been investigated as a promising, safe, and well-tolerated nonpharmacological therapy for cardio-cerebrovascular disease over the past 3 decades; variable results have been found when it is used in cerebrovascular versus cardiovascular disease. For patients with cardiovascular disease, milestone studies suggest that the roles of RIC may be limited. Recently, however, 2 large trials investigating RIC in patients with cerebrovascular disease found promising results, which may reignite the field's research prospects after its setbacks in the cardiovascular field. This perspectives article highlights several important clinical trials of RIC in the cardio-cerebrovascular disease and describes the many challenges of RIC in clinical translation. Finally, based on the available evidence, several promising research directions such as chronic RIC, early initiation in target population, improvement of compliance, better understanding of dosing, and identification of specific biomarkers are proposed and should be investigated before RIC can become applied into clinical practice for patient benefit., Competing Interests: Disclosures Dr Hess disclosed a patent for use of MAPC in neurological diseases, which has been issued and now is licensed by Athersys, Inc. The other authors report no conflicts.

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.

Background: 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., Methods: 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., Results: 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., Conclusion: Glymphatic system impaired after cerebral ischemia-reperfusion injury in mice. LRIP may play a neuroprotective role by improving glymphatic function after I/R., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Acute mesenteric ischemia (AMI) is a condition in pediatric surgery that ranges from intestine necrosis to death. Ischemic postconditioning (IPoC) methods were developed to reduce the damage caused by revascularization. This study aimed to evaluate the efficacy of these methods in an experimental weaning rat model., Methods: Thirty-two 21-day-old Wistar rats were allocated into four groups according to the surgical procedure performed: control, ischemia-reperfusion injury (IRI), local (LIPoC) and remote IPoC (RIPoC). At euthanasia, fragments of the intestine, liver, lungs, and kidneys were submitted to histological, histomorphometric, and molecular analyses., Results: In the duodenum, intestines, and kidneys histological alterations promoted by IRI were reversed by remote postconditioning method. In the distal ileum, the histomorphometric alterations could be reversed by the postconditioning methods with more evident effects promoted by the remote method. The molecular analysis found that the levels of expression of Bax (proapoptotic) and Bcl-XL (antiapoptotic) genes in the intestine were increased by IRI. These alterations were equally reversed by the postconditioning methods, with more evident effects of the remote method., Conclusions: IPoC methods positively reduced the damage caused by IRI in weaning rats.

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., Competing Interests: Conflict of interest All authors claim that there are no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

The present study was designed to investigate the efficacy of post-conditioning (POC) in the diabetic heart with myopathy (DCM) against ischaemia-reperfusion (I/R) injury in an isolated rat heart model. Present work includes three groups of male Wistar rat viz., (i) normal, (ii) diabetes mellitus (DM) and (iii) DCM and each group was subdivided into normal perfusion, I/R, and POC. Isolated heart from the rats was analysed for tissue injury, contractile function, mitochondrial function, and oxidative stress. Results demonstrated that unlike in DM heart and normal heart, POC procedure failed to recover the DCM heart from I/R induced cardiac dysfunction (measured via cardiac hemodynamics and infarct size. POC was unsuccessful in preserving mitochondrial subsarcolemmal fraction during I/R when compared with DM and normal heart. To conclude, the development of myopathy in diabetic heart abolished the cardioprotective efficacy of POC and the underlying pathology was linked with the mitochondrial dysfunction.KEY MESSAGESEarly studies reported contradicting response of diabetic heart towards post-conditioning mediated cardioprotection.Deteriorated mitochondrial function underlines the failure of post-conditioning in DCM.Efficacy of cardioprotection depends on the varying pathology of different diabetes stages.

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., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

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., (© 2022 Wiley Periodicals LLC.)

Importance: Preclinical and clinical studies have suggested a neuroprotective effect of remote ischemic conditioning (RIC), which involves repeated occlusion/release cycles on bilateral upper limb arteries; however, robust evidence in patients with ischemic stroke is lacking., Objective: To assess the efficacy of RIC for acute moderate ischemic stroke., Design, Setting, and Participants: This multicenter, open-label, blinded-end point, randomized clinical trial including 1893 patients with acute moderate ischemic stroke was conducted at 55 hospitals in China from December 26, 2018, through January 19, 2021, and the date of final follow-up was April 19, 2021., Interventions: Eligible patients were randomly assigned within 48 hours after symptom onset to receive treatment with RIC (using a pneumatic electronic device and consisting of 5 cycles of cuff inflation for 5 minutes and deflation for 5 minutes to the bilateral upper limbs to 200 mm Hg) for 10 to 14 days as an adjunct to guideline-based treatment (n = 922) or guideline-based treatment alone (n = 971)., Main Outcomes and Measures: The primary end point was excellent functional outcome at 90 days, defined as a modified Rankin Scale score of 0 to 1. All end points had blinded assessment and were analyzed on a full analysis set., Results: Among 1893 eligible patients with acute moderate ischemic stroke who were randomized (mean [SD] age, 65 [10.3] years; 606 women [34.1%]), 1776 (93.8%) completed the trial. The number with excellent functional outcome at 90 days was 582 (67.4%) in the RIC group and 566 (62.0%) in the control group (risk difference, 5.4% [95% CI, 1.0%-9.9%]; odds ratio, 1.27 [95% CI, 1.05-1.54]; P = .02). The proportion of patients with any adverse events was 6.8% (59/863) in the RIC group and 5.6% (51/913) in the control group., Conclusions and Relevance: Among adults with acute moderate ischemic stroke, treatment with remote ischemic conditioning compared with usual care significantly increased the likelihood of excellent neurologic function at 90 days. However, these findings require replication in another trial before concluding efficacy for this intervention., Trial Registration: ClinicalTrials.gov Identifier: NCT03740971.

This study intends to evaluate the characteristics of coronary microcirculatory function in patients with myocardial infarction undergoing reperfusion and its predictive value in assessing cardiac function, myocardial activity, recovery of ventricular wall motion after infarction, and distant myocardial remodeling by cardiac magnetic resonance technique (CMRI). Materials and Methods . The 293 cases of patients with myocardial infarction treated in our hospital from August 2017 to August 2021 were selected as the subjects of this retrospective study, 13 cases were shed due to transfer and moving, and the rest were divided into 140 cases each in the emergency and elective groups according to emergency percutaneous coronary intervention (PCI) and elective PCI. The patients' myocardial infarct volume ventricular volume, microcirculatory obstruction volume ventricular volume, microcirculatory obstruction volume/myocardial infarct volume, and LVEF, combined with BP and troponin T, were analysed by CMR for comparative analysis, hemodynamic, and cardiac function index differences. Results . The hemodynamics (CO, CI, SV, SI, LVSW1, and LCW) measured at different times were significantly different between the two groups; patients in the emergency group had significantly lower EDV and ESV than the elective group at 7-10 d postoperatively; and EDV, ESV, and LVEF improved in both groups after 3 months, while EDV, ESV, and LVEF improved significantly better in the emergency group than in the elective group, and the difference was statistically significant ( P < 0.05). The myocardial infarct quality, VSM score, and ventricular wall motion abnormality score were significantly lower in the emergency group than in the elective group from 7 to 10 d after PCI; myocardial infarct quality, VSM score, and ventricular wall motion abnormality score improved in both groups at 3 months after PCI; and the degree of improvement of myocardial infarct quality and VSM score was significantly better in the emergency group than in the elective group ( P < 0.05). Conclusion . Acute myocardial infarction patients with significant effect of emergency PCI treatment can be on their postmyocardial infarction left ventricular function, and in the treatment of coronary heart disease, myocardial infarction diagnosis has a certain reference value., Competing Interests: The authors declared that they have no conflicts of interest regarding this work., (Copyright © 2022 Chun Wu et al.)

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., Competing Interests: The authors have declared that no competing interests exist.

Background: Remote ischemic postconditioning (RIPostC) has recently emerged as a potential novel therapeutic strategy to achieve protection against acute myocardial infarction (AMI) injury. We aimed to evaluate the longitudinal cardioprotective effects of RIPostC on AMI using 99m Tc-MIBI SPECT myocardial perfusion imaging (MPI) and gated 18 F-FDG PET (GPET) in pigs., Methods: MI was induced in 12 Chinese pigs. RIPostC was conducted by four 5 min cycles of blood pressure cuff inflation applied to the lower limb immediately after AMI. MPI and GPET were performed longitudinally at baseline, 3rd, 14th, 28th, and 56th days after AMI. Total perfusion defect (TPD), hibernating myocardium (HM), scar, left ventricular (LV) remodeling (End diastolic volume, EDV), and bone marrow (BM) metabolic activity were analyzed, and inflammation biomarkers were measured., Results: In outcome evaluation, there was a significant attenuation in TPD (Δ value, at 14th, 28th and 56th days), HM (Δ value, at 14th, 56th days) and Scar (Δ value, at 14th, 28th days) in the RIPostC group compared with the control group (P < 0.05). Additionally, RIPostC attenuated LV enlargement (ΔEDV, at 14th day) (P < 0.05) in comparison to controls. BM 18 F-FDG uptake activity in the RIPostC group was lower than the control group (P < 0.05) at the 3rd day after AMI. There was a non-statistically significant trend of decreased MMP-2 levels in the RIPostC group post-AMI (P > 0.05)., Conclusions: RIPostC presented the longitudinal cardioprotective effects by preserving myocardial viability, reducing infarct size, attenuating LV remodeling at early stage post-AMI, and may also have an anti-inflammatory effect at the acute phase., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The present study aims to evaluate the combined effect of ischaemic postconditioning (IPostC) and nicotinamide mononucleotide (NMN) on cardioprotection and mitochondrial function in aged rats subjected to myocardial ischaemia-reperfusion (IR) injury. Sixty aged Wistar rats were randomly divided into five groups (n = 12), including sham, control, NMN, IPostC, and NMN + IPostC. Regional ischaemia was induced by 30-min occlusion of the left anterior descending coronary artery (LAD) followed by 60-min reperfusion. IPostC was applied at the onset of reperfusion, by six cycles of 10-s reperfusion/ischaemia. NMN (100 mg/kg) was intraperitoneally injected every other day for 28 days before IR. Myocardial haemodynamics and infarct size (IS) were measured, and the left ventricles samples were harvested to assess cardiac mitochondrial function. The results showed that all treatments reduced lactate dehydrogenase release compared to those of the control group. IPostC alone failed to reduce IS and myocardial function. However, NMN and combined therapy could significantly improve myocardial function and decrease the IS compared to the control animals. Moreover, the effects of combined therapy on the decrease of IS, mitochondrial reactive oxygen species (ROS), and improvement of mitochondrial membrane potential (MMP) were greater than those of stand-alone treatments. These results demonstrated that cardioprotection by combined therapy with NMN + IPostC was superior to individual treatments, and pretreatment of aged rats with NMN was able to correct the failure of IPostC in protecting the hearts of aged rats against IR injury., (© 2021 John Wiley & Sons Australia, Ltd.)

In patients with ST-segment elevation myocardial infarction (STEMI), ischemic postconditioning (iPOST) have shown ambiguous results in minimizing reperfusion injury. Previous findings show beneficial effects of iPOST in patients with STEMI treated without thrombectomy. However, it remains unknown whether the cardioprotective effect of iPOST in these patients persist on long term. In the current study, all patients were identified through the DANAMI-3-iPOST database. Patients were randomized to conventional primary percutaneous coronary intervention (PCI) or iPOST in addition to PCI. Cumulative incidence rates were calculated, and multivariable analyses stratified according to thrombectomy use were performed. The primary end point was a combination of cardiovascular mortality and hospitalization for heart failure. From 2011 to 2014, 1,234 patients with STEMI were included with a median follow-up of 4.8 years. In patients treated without thrombectomy (n = 520), the primary end point occurred in 15% (48/326) in the iPOST group and in 22% (42/194) in the conventional group (unadjusted hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.41 to 0.94, p = 0.023). In adjusted Cox analysis, iPOST remained associated with reduced long-term risk of cardiovascular mortality (HR 0.53, 95% CI 0.29 to 0.97, p = 0.039). In patients treated with thrombectomy (n = 714), there was no significant difference between iPOST (17%, 49/291) and conventional treatment (17%, 72/423) on the primary end point (unadjusted HR 1.01, 95% CI 0.70 to 1.45, p = 0.95). During a follow-up of nearly 5 years, iPOST reduced long-term occurrence of cardiovascular mortality and hospitalization for heart failure in patients with STEMI treated with PCI but without thrombectomy., Competing Interests: Disclosures Dr. Mæng has received lecture fees and advisory board fees from Novo Nordisk and a research grant from Bayer. Dr. Torp-Pedersen has received grants for studies from Bayer and Novo Nordisk. Dr. Køber has received speaker's honorarium from Novo Nordisk, AstraZeneca, Boehringer, and Novartis, unrelated to this topic. Dr. Engstrøm has received speakers/advisory board fee from Abbot Vascular, Boston Scientific, Bayer, and Novo Nordisk., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: There is a lack of data about the effects of remote ischemic postconditioning (RIPostC) on hypoxia-inducible factor-1α (HIF-1α) plasma levels after on-pump cardiac surgery (OPCS). This study aimed to measure the effects of RIPostC on postoperative HIF-1α plasma levels, cardiac markers and arterial oxygenation in patients undergoing OPCS., Methods: This single-centre randomized, double blind, controlled trial, enrolled 70 patients (35 control and 35 RIPostC). RIPostC was performed by 3 cycles (5 min of ischemia followed by 5 min of reperfusion) administered in upper arm immediately after the pump period. The primary outcome was to measure HIF-1α plasma levels: before surgery (T0), and 2 h (T1), 8 h (T2), 24 h (T3), 36 h (T4) and 48 h (T5) after RIPostC. As secondary endpoint, Troponin T, CK-MB, CPK plasma levels and PaO 2 /FiO 2 ratio were measured., Results: HIF-1α plasma levels were increased at T1-T3 compared to T0 in both groups (P < 0.001). In the RIPostC group HIF-1α increased compared to the control group: differences between means (95% CI) were 0.034 (0.006-0.06) P = 0.019 at T1; 0.041 (0.013-0.069) P = 0.005 at T2; and 0.021 (0.001-0.042) P = 0.045 at T3. PaO 2 /FiO 2 was higher in the RIPostC group than in the control group: at T3, T4 and T5. Moreover, Troponin T, CK-MB and CPK values decreased in the RIPostC group compared to the control group., Conclusions: HIF-1α plasma levels increased in control patients during for at least 36 h after OPCS. RIPostC resulted in even higher HIF-1α levels during at least the first 24 h and improved arterial oxygenation and cardiac markers., (© 2021. The Japanese Association for Thoracic Surgery.)

Background: Acute ST-elevation myocardial infarction (STEMI) is associated with a high incidence of complications as well as a considerable hospitalization rate and economic burden. Preliminary evidence suggests that remote ischemic conditioning (RIC) is a promising non-invasive intervention that may effectively and safely reduce myocardial infarct size, subsequent cardiac events and complications, and mortality. However, RIC's cardio-protective effect remains under debate, especially for single timepoint RIC programs. Adequately powered large-scale randomized controlled trials investigating clinical outcomes are thus needed to clarify the role of full disease cycle RIC programs., Methods: The intelligent "Internet Plus"-based full disease cycle remote ischemic conditioning (i-RIC) trial is a pragmatic, multicenter, randomized controlled, parallel group, clinical trial. The term, intelligent "Internet Plus"-based full disease cycle, refers to smart devices aided automatic and real-time monitoring of remote ischemic pre-, per- or post-conditioning intervention for patients with STEMI undergoing percutaneous coronary intervention (PCI). Based on this perspective, 4700 STEMI patients from five hospitals in China will be randomized to a control and an intervention group. The control group will receive PCI and usual care, including pharmacotherapy, before and after PCI. The intervention group will receive pre-, per-, and post-operative RIC combined with long-term i-RIC over a one-month period in addition. A smartphone application, an automated cuff inflation/deflation device and "Internet Plus"-based administration will be used in the long-term phase. The primary outcome is the combined cardiac death or hospitalization for heart failure rate. Secondary outcomes include clinical and functional outcomes: major adverse cardiac and cerebrovascular events rate, all-cause mortality, myocardial reinfarction rate, readmission rate for heart failure and ischemic stroke rate, unplanned revascularization rate, plasma concentration of myocardial infarction-related key biomarkers, infarct size, cardiac function, cardiopulmonary endurance, health-related quality of life, total hospital length of stay, total medical cost, and compliance with treatment regime., Discussion: The i-RIC trial is designed to test the hypothesis that clinical and functional outcomes can be improved with the i-RIC program in STEMI patients undergoing PCI. The concept of RIC is expected to be enhanced with this intelligent "Internet Plus"-based program focusing on the full disease cycle. If the i-RIC program results in superior improvement in primary and secondary outcomes, it will offer an innovative treatment option for STEMI patients and form the basis of future recommendations., Clinical Trial Registration: Chinese Clinical Trial Registry ( http://www.chictr.org.cn ): ChiCTR2000031550, 04 April 2020., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: A stroke is an acute damage to a certain area of a nerve tissue of the brain. In developed countries, it ranks second among the most often causes of death and is also the leading cause of disability. Recent findings emphasize the significant neuroprotective effect of conditioning on the course and rate of recovery after ischemic attack; however the molecular mechanism of ischemic tolerance induced by conditioning is still not completely explored., Methods and Results: The purpose of this study is an identification of changes in gene expression induced by stimulation of reaction cascades after activation of the neuroprotective mechanism using an experimental rat model of global ischemia. The induction of neuroprotective cascades was stimulated by the application of early and delayed form of remote ischemic postconditioning. The quantitative qRT-PCR method was used to assess the rate of change in ADM, BDNF, CDKN1A, CREB, GADD45G, IL6, nNOS, and TM4SF1 gene expression levels 72 h after ischemic attack. The detected results confirm the neuroprotective effect of both forms of postconditioning. Participation of neuroprotection-related gene expression changes was observed once as an early one (CREB, GADD45G), once as a delayed one (ADM, IL6), or both (BDNF, CDKN1A, nNOS, TM4SF1) postconditioning forms, depending on the particular gene., Conclusions: Our results characterize impact of ischemic tolerance on the molecular level. We predict ischemic tolerance to be consisted of complex combination of early and delayed remote postconditioning., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Ischemic stroke is one of the most lethal and severely disabling diseases that seriously affects human health and quality of life. The maintenance of self-renewal and differentiation of neural stem cells are closely related to metabolism. This study aimed to investigate whether hypoxic postconditioning (HPC) could promote neurogenesis after ischemic stroke, and to investigate the role of neuronal stem cell metabolism in HPC-induced neuroprotection. Male C57BL/6 mice were subjected to transient middle cerebral artery occlusion (MCAO), and HPC was performed for 3 h per day. Immunofluorescence staining was used to assess neurogenesis. The cell line NE-4C was used to elucidate the proliferation of neuronal stem cells in 21% O 2 or 8% O 2 . HPC promoted the recovery of neurological function in mice on day 14. HPC promoted neuronal precursor proliferation in the subventricular zone (SVZ) on day 7 and enhanced neuronal precursor migration in the basal ganglia and cortex on day 14. Fatty acid oxidation (FAO) and glycolysis of neural stem cells in the SVZ changed after MCAO with or without HPC. HPC promoted the proliferation of NE-4C stem cells, decreased FAO and increased glycolysis. All these beneficial effects of HPC were ablated by the application of an FAO activator or a glycolysis inhibitor. In conclusion, cerebral ischemia modulated the FAO and glycolysis of neural stem cells. HPC promoted the proliferation and migration of neural stem cells after MCAO, and these effects may be related to the regulation of metabolism, including FAO and glycolysis., (Copyright © 2021. Published by Elsevier Inc.)

Remote ischemic conditioning (RIC) is a promising therapeutic approach for ischemic stroke patients. It has been proven that RIC reduces infarct size and improves functional outcomes. RIC can be applied either before ischemia (pre-conditioning; RIPreC), during ischemia (per-conditioning; RIPerC) or after ischemia (post-conditioning; RIPostC). Our aim was to systematically determine the efficacy of RIC in reducing infarct volumes and define the cellular pathways involved in preclinical animal models of ischemic stroke. A systematic search in three databases yielded 50 peer-review articles. Data were analyzed using random effects models and results expressed as percentage of reduction in infarct size (95% CI). A meta-regression was also performed to evaluate the effects of covariates on the pooled effect-size. 95.3% of analyzed experiments were carried out in rodents. Thirty-nine out of the 64 experiments studied RIPostC (61%), sixteen examined RIPreC (25%) and nine tested RIPerC (14%). In all studies, RIC was shown to reduce infarct volume (- 38.36%; CI - 42.09 to - 34.62%) when compared to controls. There was a significant interaction caused by species. Short cycles in mice significantly reduces infarct volume while in rats the opposite occurs. RIPreC was shown to be the most effective strategy in mice. The present meta-analysis suggests that RIC is more efficient in transient ischemia, using a smaller number of RIC cycles, applying larger length of limb occlusion, and employing barbiturates anesthetics. There is a preclinical evidence for RIC, it is safe and effective. However, the exact cellular pathways and underlying mechanisms are still not fully determined, and its definition will be crucial for the understanding of RIC mechanism of action., (© 2021. The Author(s).)

Efforts to develop effective neuroprotective therapies for ischemic stroke have had little success to date. One promising approach to neuroprotection is ischemic postconditioning, which utilizes brief bouts of ischemia after acute ischemic stroke to elicit neuroprotection, although the mechanism is largely unknown. As the primary components of transient ischemia are local hypoxia and acidosis, and hypoxic postconditioning has had little success, it is possible that the acidosis component may be the primary driver. To address the evidence behind this, we performed a systematic review of preclinical studies focused on the neuroprotective role of transient acidosis after ischemia. Animal studies demonstrated that mild-to-moderate acidosis after ischemic events led to better functional neurologic outcomes with reduced infarct volumes, while severe acidosis often led to cerebral edema and worse functional outcomes. In vitro studies demonstrated that mild-to-moderate acidosis improves neuronal survival largely through two means: (1) inhibition of harmful superoxide formation in the excitotoxic pathway and (2) remodeling neuronal mitochondria to allow for efficient ATP production (i.e., oxidative phosphorylation), even in the absence of oxygen. Similar to the animal studies, acidotic postconditioning in humans would entail short cycles of carbon dioxide inhalation, which has already been demonstrated to be safe as part of a hypercapnic challenge when measuring cerebrovascular reactivity. Due to the preclinical efficacy of acidotic postconditioning, its relatively straightforward translation into humans, and the growing need for neuroprotective therapies, future preclinical studies should focus on filling the current knowledge gaps that are currently restricting the development of phase I/II clinical trials., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Intestinal ischemia reperfusion (I/R) injury is a tissue and organ injury that frequently occurs during surgery and significantly contributes to the pathological processes of severe infection, injury, shock, cardiopulmonary insufficiency and other diseases. However, the mechanism of intestinal I/R injury remains to be elucidated. A mouse model of intestinal I/R injury was successfully established and the model mice were treated with remote ischemic post‑conditioning (RIPOC) and/or an ERK inhibitor (CC‑90003), respectively. Histopathological changes of the intestinal mucosa were determined by hematoxylin and eosin staining. In addition, the levels of high‑mobility group box 1 (HMGB1) and receptor for advanced glycation end products (RAGE) expression were confirmed by reverse transcription‑quantitative polymerase chain reaction, western blotting and immunohistochemistry assays. The levels of antioxidants, oxidative stress markers (8‑OHdG) and interleukin 1 family members were evaluated by ELISA assays and the levels of NF‑κB pathway proteins were analyzed by western blotting. The data demonstrated that RIPOC could attenuate the histopathological features of intestinal mucosa in the intestinal I/R‑injury mouse models via the ERK pathway. It was also revealed that HMGB1 and RAGE expression in the mouse models could be markedly reduced by RIPOC (P<0.05) and that these reductions were associated with inhibition of the ERK pathway. Furthermore, it was demonstrated that RIPOC produced significant antioxidant and anti‑inflammatory effects following an intestinal I/R injury and that these effects were mediated via the ERK pathway (P<0.05). In addition, RIPOC was demonstrated to suppress the NF‑κB (p65)/NLR family pyrin domain containing 3 (NLRP3) inflammatory pathways in the intestinal I/R injury mouse models via the ERK pathway. The findings of the present study demonstrated that RIPOC helped to protect mice with an intestinal I/R injury by downregulating the ERK pathway.

Post-conditioning with sevoflurane, a volatile anesthetic, has been proved to be neuroprotective against hypoxic-ischemic brain injury (HIBI). Our previous research showed that autophagy is over-activated in a neonatal HIBI rat model, and inhibition of autophagy confers neuroprotection. There is increasing recognition that autophagy can be stimulated by activating endoplasmic reticulum (ER) stress. Herein, we purposed to explore: i) the association of ER stress with autophagy in the setting of neonatal HIBI; and ii) the possible roles of ER stress-triggered autophagy, as well as IRE1 signaling in the neuroprotection of sevoflurane post-conditioning against neonatal HIBI. Seven-day-old rats underwent ligation of the left common artery, and a subsequent 2 h hypoxia (8% O2/92% N2). The association of ER stress with autophagy was examined by ER stress inducer (tunicamycin), 4-PBA (ER stress inhibitor), or 3-MA (autophagy inhibitor). Rats in the sevoflurane post-conditioning groups were treated with 2.4% sevoflurane for 30 min after HIBI stimulation. The roles of ER stress-mediated autophagy, as well as the IRE1-JNK-beclin1 signaling cascade in the neuroprotection afforded by sevoflurane were explored by ER stress inducer (tunicamycin) and the IRE1 inhibitor (STF-083010). HIBI over-activated ER stress and autophagy in neonatal rats. HIBI-induced autophagy was significantly aggravated by tunicamycin but blocked by 4-PBA; however, HIBI-induced ER stress was not affected by 3-MA. Sevoflurane post-conditioning significantly alleviated ER stress, autophagy, cell apoptosis, and cognitive impairments, which were remarkably abolished by tunicamycin. Also, tunicamycin blocked sevoflurane-induced downregulation of IRE1-JNK-beclin1 signaling pathway. Whereas, IRE1 inhibitor could reverse the effects of tunicamycin. ER stress contributes to autophagy induced by HIBI. Furthermore, sevoflurane post-conditioning significantly protects against HIBI in neonatal rats by inhibiting ER stress-mediated autophagy via IRE1-JNK-beclin1 signaling cascade., (Copyright © 2021. Published by Elsevier Ltd.)

Objective : Exercise is an essential rehabilitative strategy after stroke butits implementation is limited as its very early use can exacerbate damage and is restricted by patient disability. Remote Ischemic Conditioning (RIC) is a safe alternative for post-stroke neuroprotetion. The present study investigated the neurorehabilitative benefits of early RIC followed by exercise (RICE) therapy. Methods : 48 adult male Sprague-Dawley rats were divided into groups: 1) sham, 2) stroke, 3) stroke with RICE at day 3 (RIC 6 hours after reperfusion followed by exercise days 3 to 28), 4) stroke with exercise at day 3 (exercise days 3 to 28), and 5) stroke with RICE at day 1 (RIC 6 hours after reperfusion followed by exercise days 1 to 28), 6) stroke with exercise at day 1 (exercise days 1 to 28 after reperfusion). Long-term functional outcomes were determined by grid walk, rota-rod, adhesive tape touch, and Morris water maze. Levels of mRNA and proteins of neuroplasticity, synaptogenesis, and angiogenesis, were determined. Results : As compared to exercise only, animals that underwent RICE had significant improvements in functional outcomes after stroke. These improvements were most significant in groups that had the later initiation of exercise. In addition, all treatment groups showed significant increases in mRNA and protein expression of the target molecules for neuroplasticity, synaptogenesis, and angiogenesis, while further significant increases were observed after RICE following ischemic stroke. Conclusions : RICE, a novel therapy that supplements RIC prior to exercise, is superiorly effective in inducing rehabilitation after stroke as compared to the traditional exercise monotherapy rehabilitation in rats with ischemic brain injury.