Research progress on the mechanism of action and clinical application of remote ischemic post-conditioning for acute ischemic stroke.

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.

DJ-1 preserves ischemic postconditioning-induced cardioprotection in STZ-induced type 1 diabetic rats: role of PTEN and DJ-1 subcellular translocation.

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.

The Role of the JAK-STAT Signaling Pathway in the Protective Effects of Hepatic Ischemia Post-conditioning Against the Injury Induced by Ischemia/Reperfusion in the Rat Liver.

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<0.05, respectively). There was also downregulation of the Bax/Bcl2 ratio in the rats exposed to IR+hepatic IPOC compared with those in the IR group (P<0.05). However, TOFA, an inhibitor of JAK-STAT activity, inhibited the protective effect of hepatic IPOC. 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.

Mitochondrial Calcium Uniporter (MCU) is Involved in an Ischemic Postconditioning Effect Against Ischemic Reperfusion Brain Injury in Mice.

The phenomenon of ischemic postconditioning (PostC) is known to be neuroprotective against ischemic reperfusion (I/R) injury. One of the key processes in PostC is the opening of the mitochondrial ATP-dependent potassium (mito-KATP) channel and depolarization of the mitochondrial membrane, triggering the release of calcium ions from mitochondria through low-conductance opening of the mitochondrial permeability transition pore. Mitochondrial calcium uniporter (MCU) is known as a highly sensitive transporter for the uptake of Ca2+ present on the inner mitochondrial membrane. The MCU has attracted attention as a new target for treatment in diseases, such as neurodegenerative diseases, cancer, and ischemic stroke. We considered that the MCU may be involved in PostC and trigger its mechanisms. This research used the whole-cell patch-clamp technique on hippocampal CA1 pyramidal cells from C57BL mice and measured changes in spontaneous excitatory post-synaptic currents (sEPSCs), intracellular Ca2+ concentration, mitochondrial membrane potential, and N-methyl-D-aspartate receptor (NMDAR) currents under inhibition of MCU by ruthenium red 265 (Ru265) in PostC. Inhibition of MCU increased the occurrence of sEPSCs (p = 0.014), NMDAR currents (p < 0.001), intracellular Ca2+ concentration (p < 0.001), and dead cells (p < 0.001) significantly after reperfusion, reflecting removal of the neuroprotective effects in PostC. Moreover, mitochondrial depolarization in PostC with Ru265 was weakened, compared to PostC (p = 0.004). These results suggest that MCU affects mitochondrial depolarization in PostC to suppress NMDAR over-activation and prevent elevation of intracellular Ca2+ concentrations against I/R injury.

Remote Ischemic Postconditioning-Mediated Neuroprotection against Stroke by Promoting Ketone Body-Induced Ferroptosis Inhibition.

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.

Middle-age abolishes cardioprotection conferred by thioredoxin-1 in mice.

Thioredoxin-1 (Trx1) has cardioprotective effects on ischemia/reperfusion (I/R) injury, although its role in ischemic postconditioning (PostC) in middle-aged mice is not understood. This study aimed to evaluate if combining two cardioprotective strategies, such as Trx1 overexpression and PostC, could exert a synergistic effect in reducing infarct size in middle-aged mice. Young or middle-aged wild-type mice (Wt), transgenic mice overexpressing Trx1, and dominant negative (DN-Trx1) mutant of Trx1 mice were used. Mice hearts were subjected to I/R or PostC protocol. Infarct size, hydrogen peroxide (H2O2) production, protein nitration, Trx1 activity, mitochondrial function, and Trx1, pAkt and pGSK3ß expression were measured. PostC could not reduce infarct size even in the presence of Trx1 overexpression in middle-aged mice. This finding was accompanied by a lack of Akt and GSK3ß phosphorylation, and Trx1 expression (in Wt group). Trx1 activity was diminished and H2O2 production and protein nitration were increased in middle-age. The respiratory control rate dropped after I/R in Wt-Young and PostC restored this value, but not in middle-aged groups. Our results showed that Trx1 plays a key role in the PostC protection mechanism in young but not middle-aged mice, even in the presence of Trx1 overexpression.

Obesity as a Limiting Factor for Remote Ischemic Postconditioning-Mediated Neuroprotection after Stroke.

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.

Remote ischemic postconditioning alleviates cerebral ischemic injury through SERCA2/endoplasmic reticulum stress-mediated apoptosis.

Remote ischemic postconditioning (RIPostC) alleviates brain ischemic injury through several pathways, including endoplasmic reticulum (ER) stress modulation. Sarco endoplasmic reticulum Ca2+ -ATPase(SERCA2) which plays vital role in calcium homeostasis regulation could modulate ER stress logically. This study aimed to investigate whether RIPostC exerts its neuroprotective effect by reducing ER stress mediated by SERCA2. Male SD rats underwent transient middle cerebral artery occlusion (tMCAO) for 2 h followed by reperfusion, with the RIPostC group undergoing 3 cycles of bilateral femoral artery clamping and reperfusion at the beginning of reperfusion. Stroke outcome was assessed based on infarct volume and neurological function evaluation. Protein levels of SERCA2 and other ER stress markers were measured using Western blotting, immunofluorescence, and immunohistochemistry techniques. Compared to the sham group, we observed that RIPostC can effectively reduce cerebral infarct volume after I/R (34.55%: 21.03%; p = .004) and improve neurological function deficit (9.67:12.5; p = .029). Additionally, RIPostC increased SERCA2 protein expression and decreased the protein level of glucose-regulated protein 78 (GRP78), phosphorylation of eukaryotic translation initiation factor 2α (p-eIF2α) and CCAAT/EBP homologous protein (CHOP). Furthermore, B-cell lymphoma-2 (Bcl-2) expression was increased, while Bcl-2-associated X protein (Bax) and cleaved-caspase-3 was decreased in response to application of RIPostC. Our results suggest that RIPostC improves the prognosis of tMCAO rats, possibly by inhibiting the ER stress mediated by SERCA2, facilitating apoptosis downregulation. The significance of this study is to provide a theoretical basis for further exploring the protective mechanism of ischemic stroke by RIPostC. RESEARCH HIGHLIGHTS: Our results suggest that RIPostC improves the prognosis of tMCAO rats, possibly by inhibiting the ER stress mediated by SERCA2, facilitating apoptosis downregulation, thus achieving a neuroprotective effect.

Cerebral protective effect of in situ and remote ischemic postconditioning on ischemic stroke rat via the TGFß1-Smad2/3 signaling pathway.

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 TGFß1, 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 TGFß1, increased protein levels of TGFß1 and decreased levels of p-Smad2/3 and smad3 following RIP intervention. We showed that the TGFß1-Smad2/3 signaling pathway was associated with the cerebral protection of ischemic postconditioning.

Effect of remote ischemic postconditioning on left ventricular ejection fraction in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.

BACKGROUND: Ischemic conditioning may help patients with ST-segment elevation myocardial infarction (STEMI) to limit ventricular remodeling. OBJECTIVES: To investigate the effect of remote ischemic postconditioning (RIPC) on left ventricular function during primary percutaneous coronary intervention (PPCI) in patients with STEMI. MATERIAL AND METHODS: Pre- and post-test intervention study with a total of 60 STEMI patients. Patients were divided in two groups: with and without RIPC. RESULTS: During the 6-month follow-up, a significant difference in left ventricular ejection fraction was observed in patients who underwent PPCI, which was higher in the group with RIPC in comparison with the group without RIPC: 1.0% (-1.0 to 4.3) vs. -1.0% (-4.0 to 1.3), p = 0.033. In addition, at 6-month measurement, left ventricular end-systolic volume in patients without RIPC was higher in comparison with their counterparts: 79.3 ± 30.5 mL vs. 64.4 ± 21.4 mL, p = 0.032. CONCLUSIONS: RIPC shows favorable effects on left ventricular function and, therefore, in the future, it could be a potential cardioprotective strategy against ischemia-reperfusion injury in STEMI patients.

ANTECEDENTES: En los pacientes con infarto agudo de miocardio con elevación del segmento ST (IAMCEST), el acondicionamiento isquémico puede ayudar a limitar la remodelación ventricular. OBJETIVOS: Investigar el efecto del posacondicionamiento isquémico remoto (PAIR) en la función del ventrículo izquierdo durante la intervención coronaria percutánea primaria (ICPP) en pacientes con IAMCEST. MATERIAL Y MÉTODOS: Estudio de intervención pre y posprueba con un total de 60 pacientes con IAMCEST. Los pacientes fueron divididos en dos grupos: con y sin PAIR. RESULTADOS: En el seguimiento de seis meses se observó una diferencia significativa en la fracción de eyección del ventrículo izquierdo en pacientes con ICPP, la cual fue mayor en el grupo con PAIR en comparación con el grupo sin PAIR: 1.0 (−1.0 a 4.3) versus −1.0 (−4.0 a ­1.3), p = 0.033. En la medición de seis meses, el volumen sistólico final del ventrículo izquierdo en los pacientes sin PAIR fue mayor en comparación con el grupo homólogo: 79.3 ± 30.5 mL versus 64.4 ± 21.4 mL, p = 0.032. CONCLUSIONES: PAIR muestra efectos favorables en la función ventricular izquierda y, por lo tanto, en el futuro podría ser una estrategia cardioprotectora potencial contra la lesión por isquemia-reperfusión en pacientes con IAMCEST.

Remote limb ischemic postconditioning inhibits microglia pyroptosis by modulating HGF after acute ischemia stroke.

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.

Ischemic Postconditioning Confers No Benefit to Left Ventricular Systolic Function: A Meta-Analysis of Cardiac Magnetic Resonance Imaging Results.

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.

Anti-Inflammatory and Antipruritic Effects of Remote Ischaemic Postconditioning in a Mouse Model of Experimental Allergic Contact Dermatitis.

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.

Efecto del posacondicionamiento isquémico remoto sobre la fracción de eyección del ventrículo izquierdo en pacientes con infarto de miocardio con elevación del segmento ST sometidos a intervención coronaria percutánea primaria / Effect of remote ischemic postconditioning on left ventricular ejection fraction in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention

Resumen Antecedentes: En los pacientes con infarto agudo de miocardio con elevación del segmento ST (IAMCEST), el acondicionamiento isquémico puede ayudar a limitar la remodelación ventricular. Objetivos: Investigar el efecto del posacondicionamiento isquémico remoto (PAIR) en la función del ventrículo izquierdo durante la intervención coronaria percutánea primaria (ICPP) en pacientes con IAMCEST. Material y métodos: Estudio de intervención pre y posprueba con un total de 60 pacientes con IAMCEST. Los pacientes fueron divididos en dos grupos: con y sin PAIR. Resultados: En el seguimiento de seis meses se observó una diferencia significativa en la fracción de eyección del ventrículo izquierdo en pacientes con ICPP, la cual fue mayor en el grupo con PAIR en comparación con el grupo sin PAIR: 1.0 (−1.0 a 4.3) versus −1.0 (−4.0 a –1.3), p = 0.033. En la medición de seis meses, el volumen sistólico final del ventrículo izquierdo en los pacientes sin PAIR fue mayor en comparación con el grupo homólogo: 79.3 ± 30.5 mL versus 64.4 ± 21.4 mL, p = 0.032. Conclusiones: PAIR muestra efectos favorables en la función ventricular izquierda y, por lo tanto, en el futuro podría ser una estrategia cardioprotectora potencial contra la lesión por isquemia-reperfusión en pacientes con IAMCEST.

Abstract Background: Ischemic conditioning may help patients with ST-segment elevation myocardial infarction (STEMI) to limit ventricular remodeling. Objectives: To investigate the effect of remote ischemic postconditioning (RIPC) on left ventricular function during primary percutaneous coronary intervention (PPCI) in patients with STEMI. Material and methods: Pre- and post-test intervention study with a total of 60 STEMI patients. Patients were divided in two groups: with and without RIPC. Results: At 6-month follow-up evaluation, a significant difference in left ventricular ejection fraction was observed in patients who underwent PPCI, which was higher in the group with RIPC in comparison with the group without RIPC: 1.0 (−1.0 to 4.3) vs. −1.0 (−4.0 to –1.3), p = 0.033. In addition, at 6-month measurement, left ventricular end-systolic volume in patients without RIPC: was higher in comparison with their counterparts: 79.3 ± 30.5 mL versus 64.4 ± 21.4 mL, p = 0.032. Conclusions: RIPC shows favorable effects on left ventricular function and, therefore, in the future, it could be a potential cardioprotective strategy against ischemia-reperfusion injury in STEMI patients.

Brain Protection Effects of Mild Hypothermia Combined with Distant Ischemic Postconditioning and Thrombolysis in Patients with Acute Ischemic Stroke.

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-1ß, 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.

The mechanism and targeted intervention of the HIF-1 pathway in improving atherosclerotic heart's sensitivity to ischemic postconditioning.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Safety and Tolerability of Direct Ischemic Postconditioning Following Thrombectomy for Acute Ischemic Stroke.

BACKGROUND: Experimental studies have demonstrated the neuroprotection of ischemic postconditioning (IPostC) in acute ischemic stroke by attenuating ischemia-reperfusion injury. This study aimed to investigate the safety and tolerability of direct IPostC in both a dog model and patients with acute ischemic stroke treated with thrombectomy. METHODS: The study involved 2 parts. First, IPostC was induced by repeated balloon inflation and deflation in dogs, where a low-pressure balloon was navigated to the anterior spinal artery, and 4 cycles of 5-minute ischemia followed by 5-minute reperfusion were performed. Vascular injuries were assessed using angiography and vascular tissue specimens. Then, a 3+3 dose-escalation trial was conducted in patients with acute ischemic stroke following successful thrombectomy recanalization. Patients received direct IPostC with ischemia and reperfusion durations in progressive increments of 0, 1, 2, 3, 4, and 5 minutes ×4 cycles. Major adverse responses were defined as vessel perforation, rupture, dissection, reocclusion, severe vasospasm, thrombotic events, and rupture of the balloon. RESULTS: IPostC was investigated in 4 dogs. No vessel perforation or rupture, dissection, or vasospasm was observed under the angiography. Only 1 vessel experienced mild injury between the intima and the internal elastic membrane detected on a histopathologic slide. Then, 18 patients were recruited. The duration of IPostC was progressively escalated with no major response happened. No patient experienced agitation, discomfort, or other tolerability issues. Five patients (27.8%) experienced any intracranial hemorrhage after thrombectomy, and 1 (5.6%) was symptomatic. At 3-month follow-up, no patient died, and 9 patients (50%) achieved functional independence. CONCLUSIONS: Direct IPostC inducing by 4 cycles of 5-minute ischemia followed by 5-minute reperfusion is safe, feasible, and tolerable in patients with acute ischemic stroke treated with thrombectomy. Further investigations are needed to determine the safety and preliminary efficacy of direct IPostC. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT05153655.

Remote Ischemic Conditioning: Challenges and Opportunities.

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.