Time­dependent changes in blood cells, NIHSS and mRS according to reperfusion treatment type in stroke patients who developed hemorrhagic complication.

Hemorrhagic complications may be seen following reperfusion therapy with rtPA and/or thrombectomy after acute ischemic stroke (AIS). Neutrophils, lymphocytes, and platelets have important roles in the inflammatory and immune responses that develop in these patients. We investigated time­dependent changes in blood cells, NIHSS and mRS values according to type of reperfusion therapy in AIS patients who developed cerebral hemorrhage. In AIS patients who underwent rtPA and/or thrombectomy and developed cerebral hemorrhage within the first 24 hours after treatment, leukocyte, neutrophil, lymphocyte, platelet counts and their ratios were recorded on admission, 1st, 3rd, and 7th days. NIHSS values on admission, 3rd days and mRS values on admission, discharge, and the 3rd month were recorded. These values were compared according to the type of reperfusion therapy. Out of 436 AIS patients, rtPA was applied in 50.5%, thrombectomy in 28.2%, and rtPA+thrombectomy in 21.3%. Hemorrhage developed in 25.5% of the patients. Patients treated with thrombectomy had a greater rate of cerebral hemorrhage. Pre­stroke mRS values were lower in all therapy types than mRS scores at discharge and the 3rd month. The NIHSS scores did not differ significantly in 3 days. Depending on the type of reperfusion treatment, there are a few time­dependent significant changes observed in the blood cell counts and ratios. In conclusion, there is a relation between the type of reperfusion therapy and the time­dependent changes in blood cells and ratios as well as mRS scores among AIS patients who have undergone rtPA and/or thrombectomy and developed cerebral hemorrhage.

Association of Time to Thrombolysis With Early Reperfusion After Alteplase and Tenecteplase in Patients With Large Vessel Occlusion.

BACKGROUND AND OBJECTIVES: Early treatment with intravenous alteplase increases the probability of lytic-induced reperfusion in large vessel occlusion (LVO) patients. The relationship of tenecteplase-induced reperfusion and the timing of thrombolytic administration has not been explored. In this study, we performed a comparative analysis of tenecteplase and alteplase reperfusion rates and assessed their relationship to the time of thrombolytic administration. METHODS: Patients who were initially treated with a thrombolytic within 4.5 hours of symptom onset were pooled from the Royal Melbourne Stroke Registry, EXTEND-IA, EXTEND-IA TNK, and EXTEND-IA TNK part 2 trials. The primary outcome, thrombolytic-induced reperfusion, was defined as the absence of retrievable thrombus or >50% reperfusion at initial angiographic assessment (or repeat CT perfusion/angiography). We compared the treatment effect of tenecteplase and alteplase through fixed-effects Poisson regression modelling. RESULTS: Among 846 patients included in the primary analysis, early reperfusion was observed in 173 (20%) patients (tenecteplase: 98/470 [21%], onset-to-thrombolytic time: 132 minutes [interquartile range (IQR): 99-170], and thrombolytic-to-assessment time: 61 minutes [IQR: 39-96]; alteplase: 75/376 [19%], onset-to-thrombolytic time: 143 minutes [IQR: 105-180], thrombolytic-to-assessment time: 92 minutes [IQR: 63-144]). Earlier onset-to-thrombolytic administration times were associated with an increased probability of thrombolytic-induced reperfusion in patients treated with either tenecteplase (adjusted risk ratio [aRR] 1.05 per 15 minutes [95% confidence interval (CI) 1.00-1.12] or alteplase (aRR 1.06 per 15 minutes [95% CI 1.00-1.13]). Tenecteplase remained associated with higher rates of reperfusion vs alteplase after adjustment for onset-to-thrombolytic time, occlusion site, thrombolytic-to-assessment time, and study as a fixed effect, (adjusted incidence rate ratio: 1.41 [95% CI 1.02-1.93]). No significant treatment-by-time interaction was observed (p = 0.87). DISCUSSION: In patients with LVO presenting within 4.5 hours of symptom onset, earlier thrombolytic administration increased successful reperfusion rates. Compared with alteplase, tenecteplase was associated with a higher probability of lytic-induced reperfusion, independent of onset-to-lytic administration times. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifiers: NCT02388061, NCT03340493. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among patients with LVO receiving a thrombolytic, reperfusion was more likely with tenecteplase than alteplase.

Tanshinone IIA Alleviates Traumatic Brain Injury by Reducing Ischemia‒Reperfusion via the miR-124-5p/FoxO1 Axis.

Background: Cerebral ischemia-reperfusion injury is a common complication of ischemic stroke that affects the prognosis of patients with ischemic stroke. The lipid-soluble diterpene Tanshinone IIA, which was isolated from Salvia miltiorrhiza, has been indicated to reduce cerebral ischemic injury. In this study, we investigated the molecular mechanism of Tanshinone IIA in alleviating reperfusion-induced brain injury. Methods: Middle cerebral artery occlusion animal models were established, and neurological scores, tetrazolium chloride staining, brain volume quantification, wet and dry brain water content measurement, Nissl staining, enzyme-linked immunosorbent assay, flow cytometry, western blotting, and reverse transcription-quantitative polymerase chain reaction were performed. The viability of cells was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assays, while cell damage was measured by lactate dehydrogenase release in the in vitro oxygen glucose deprivation model. In addition, enzyme-linked immunosorbent assay, flow cytometry, western blotting, and reverse transcription-quantitative polymerase chain reaction were used to evaluate the therapeutic effect of Tanshinone IIA on ischemia/reperfusion (I/R) induced brain injury, as well as its effects on the inflammatory response and neuronal apoptosis, in vivo and in vitro. Furthermore, this study validated the targeting relationship between miR-124-5p and FoxO1 using a dual luciferase assay. Finally, we examined the role of Tanshinone IIA in brain injury from a molecular perspective by inhibiting miR-124-5p or increasing FoxO1 levels. Results: After treatment with Tanshinone IIA in middle cerebral artery occlusion-reperfusion (MCAO/R) rats, the volume of cerebral infarction was reduced, the water content of the brain was decreased, the nerve function of the rats was significantly improved, and the cell damage was significantly reduced. In addition, Tanshinone IIA effectively inhibited the I/R-induced inflammatory response and neuronal apoptosis, that is, it inhibited the expression of inflammatory cytokines IL-1ß, IL-6, TNF-α, decreased the expression of apoptotic protein Bax and Cleaved-caspase-3, and promoted the expression of antiapoptotic protein Bcl-2. In vitro oxygen-glucose deprivation/reoxygenation (OGD/R) cell model, Tanshinone IIA also inhibited the expression of inflammatory factors in neuronal cells and inhibited the occurrence of neuronal apoptosis. In addition, Tanshinone IIA promoted the expression of miR-124-5p. Transfection of miR-124-5p mimic has the same therapeutic effect as Tanshinone IIA and positive therapeutic effect on OGD cells, while transfection of miR-124-5p inhibitor has the opposite effect. The targeting of miR-124-5p negatively regulates FoxO1 expression. Inhibition of miR-124-5p or overexpression of FoxO1 can weaken the inhibitory effect of Tanshinone IIA on brain injury induced by I/R, while inhibition of miR-124-5p and overexpression of FoxO1 can further weaken the effect of Tanshinone IIA. Conclusion: Tanshinone IIA alleviates ischemic-reperfusion brain injury by inhibiting neuroinflammation through the miR-124-5p/FoxO1 axis. This finding provides a theoretical basis for mechanistic research on cerebral ischemia-reperfusion injury.

An engineered poly(A) tail attenuates gut ischemia/reperfusion-induced acute lung injury.

BACKGROUND: Gut ischemia/reperfusion causes the release of damage-associated molecular patterns, leading to acute lung injury and high mortality. Cold-inducible ribonucleic acid-binding protein is a ribonucleic acid chaperon that binds the polyadenylation tail of messenger ribonucleic acid intracellularly. Upon cell stress, cold-inducible ribonucleic acid-binding protein is released, and extracellular cold-inducible ribonucleic acid-binding protein acts as a damage-associated molecular pattern, worsening inflammation. To inhibit extracellular cold-inducible ribonucleic acid-binding protein, we have recently developed an engineered polyadenylation tail named A12. Here, we sought to investigate the therapeutic potential of A12 in gut ischemia/reperfusion-induced acute lung injury. METHODS: Male C57BL6/J mice underwent superior mesenteric artery occlusion and were treated with intraperitoneal A12 (0.5 nmol/g body weight) or vehicle at the time of reperfusion. Blood and lungs were collected 4 hours after gut ischemia/reperfusion. Systemic levels of extracellular cold-inducible ribonucleic acid-binding protein, interleukin-6, aspartate transaminase, alanine transaminase, and lactate dehydrogenase were determined. The pulmonary gene expression of cytokines (interleukin-6, interleukin-1ß) and chemokines (macrophage-inflammatory protein-2, keratinocyte-derived chemokine) was also assessed. In addition, lung myeloperoxidase, injury score, and cell death were determined. Mice were monitored for 48 hours after gut ischemia/reperfusion for survival assessment. RESULTS: Gut ischemia/reperfusion significantly increased the serum extracellular cold-inducible ribonucleic acid-binding protein levels. A12 treatment markedly reduced the elevated serum interleukin-6, alanine transaminase, aspartate transaminase, and lactate dehydrogenase by 53%, 23%, 23%, and 24%, respectively, in gut ischemia/reperfusion mice. A12 also significantly decreased cytokine and chemokine messenger ribonucleic acids and myeloperoxidase activity in the lungs of gut ischemia/reperfusion mice. Histological analysis revealed that A12 attenuated tissue injury and cell death in the lungs of gut ischemia/reperfusion mice. Finally, administration of A12 markedly improved the survival of gut ischemia/reperfusion mice. CONCLUSION: A12, a novel extracellular cold-inducible ribonucleic acid-binding protein inhibitor, diminishes inflammation and mitigates acute lung injury when employed as a treatment during gut ischemia/reperfusion. Hence, the targeted approach toward extracellular cold-inducible ribonucleic acid-binding protein emerges as a promising therapeutic strategy for alleviating gut ischemia/reperfusion-induced acute lung injury.

Reperfusion in Patients With ST-Segment-Elevation Myocardial Infarction With Cardiogenic Shock and Prolonged Interhospital Transport Times.

BACKGROUND: In patients with ST-segment-elevation myocardial infarction complicated by cardiogenic shock, primary percutaneous coronary intervention (pPCI) is the preferred revascularization option. Little is known about the efficacy and safety of a pharmacoinvasive approach for patients with cardiogenic shock presenting to a non-PCI hospital with prolonged interhospital transport times. METHODS: In a retrospective analysis of geographically extensive ST-segment-elevation myocardial infarction network (2006-2021), 426 patients with cardiogenic shock and ST-segment-elevation myocardial infarction presented to a non-PCI-capable hospital and underwent reperfusion therapy (53.8% pharmacoinvasive and 46.2% pPCI). The primary clinical outcome was a composite of in-hospital mortality, renal failure requiring dialysis, cardiac arrest, or mechanical circulatory support, and the primary safety outcome was major bleeding defined as an intracranial hemorrhage or bleeding that required transfusion was compared in an inverse probability weighted model. The electrocardiographic reperfusion outcome of interest was the worst residual ST-segment-elevation. RESULTS: Patients with pharmacoinvasive treatment had longer median interhospital transport (3 hours versus 1 hour) and shorter median symptom-onset-to-reperfusion (125 minute-to-needle versus 419 minute-to-balloon) times. ST-segment resolution ≥50% on the postfibrinolysis ECG was 56.6%. Postcatheterization, worst lead residual ST-segment-elevation <1 mm (57.3% versus 46.3%; P=0.01) was higher in the pharmacoinvasive compared with the pPCI cohort, but no differences were observed in the worst lead ST-segment-elevation resolution ≥50% (77.4% versus 81.8%; P=0.57). The primary clinical end point was lower in the pharmacoinvasive cohort (35.2% versus 57.0%; inverse probability weighted odds ratio, 0.44 [95% CI, 0.26-0.72]; P<0.01) compared with patients who received pPCI. An interaction between interhospital transfer time and reperfusion strategy with all-cause mortality was observed, favoring a pharmacoinvasive approach with transfer times >60 minutes. The incidence of the primary safety outcome was 10.1% in the pharmacoinvasive arm versus 18.7% in pPCI (adjusted odds ratio, 0.41 [95% CI, 0.14-1.09]; P=0.08). CONCLUSIONS: In patients with ST-segment-elevation myocardial infarction presenting with cardiogenic shock and prolonged interhospital transport times, a pharmacoinvasive approach was associated with improved electrocardiographic reperfusion and a lower rate of death, dialysis, or mechanical circulatory support without an increase in major bleeding.

Transmission of high arterial pressure into renal microvessels during venous-clamping augments ischaemia/reperfusion-induced acute kidney injury in anaesthetized rats.

AIM: In two recent studies, we observed that a 30-min renal vein clamping caused formation of interstitial haemorrhagic congestion in ischaemic and ischaemic/reperfused kidney along with the development of severer acute kidney injury (AKI) than renal artery or pedicle clamping. It was suggested that the transmission of high arterial pressure into renal microvessels during vein occlusion probably causes the occurrence of interstitial haemorrhagic congestion that augments AKI. The present investigation aimed to evaluate this suggestion by reducing renal perfusion pressure (RPP) during renal venous occlusion. METHODS: Anaesthetized male Sprague-Dawley rats were divided into three groups (n = 8), which underwent a 2-h reperfusion period following 30-min bilateral renal venous clamping along with reduced RPP (VIR-rRPP group) or without reduced RPP (VIR group) and an equivalent period after sham-operation (Sham group). RESULTS: The VIR-rRPP group compared with VIR group had lower levels of kidney malondialdehyde and tissue damages as epithelial injuries of proximal tubule and thick ascending limb, vascular congestion, intratubular cast and oedema, along with the less reductions in renal blood flow, creatinine clearance, Na+ -reabsorption, K+ and urea excretion, urine osmolality and free-water reabsorption. Importantly, the formation of intensive interstitial haemorrhagic congestion in the VIR group was not observed in the VIR-rRPP group. CONCLUSION: These results indicate that the transmission of high arterial pressure into renal microvessels during venous occlusion leads to rupturing of their walls and the formation of interstitial haemorrhagic congestion, which has an augmenting impact on ischaemia/reperfusion-induced renal structural damages and haemodynamic, excretory and urine-concentrating dysfunctions.

Biomimetic Lung-Targeting Nanoparticles with Antioxidative and Nrf2 Activating Properties for Treating Ischemia/Reperfusion-Induced Acute Lung Injury.

Ischemia/reperfusion (IR)-induced acute lung injury (ALI) has a high mortality rate. Reactive oxygen species (ROS) play a crucial role in causing cellular damage and death in IR-induced ALI. In this work, we developed a biomimetic lung-targeting nanoparticle (PC@MB) as an antioxidative lung protector for treating IR-induced ALI. PC@MBs showed excellent ROS scavenging and Nrf2 activation properties, along with a lung-targeting function through autologous cell membrane coating. The PC@MBs exhibited an impressive antioxidative and pulmonary protective role via redox homeostasis recovery through Nrf2 and heme oxygenase-1 activation. PC@MBs could maintain cell viability by effectively scavenging the intracellular ROS and restoring the redox equilibrium in the lesion. In the IR mouse model, the PC@MBs preferentially accumulated in the lung and distinctly repaired the pneumonic damage. Our strategy has the potential to offer a promising therapeutic paradigm for treating IR-induced ALI through the incorporation of different therapeutic mechanisms.

Acute Dysphagia Following Reperfusion Therapies: A Prospective Pilot Cohort Study.

Dysphagia is a well-documented sequela of stroke. Recent advancements in medical treatments for stroke include reperfusion therapies (endovascular thrombectomy (EVT) and thrombolysis). As outcomes following reperfusion therapies are typically measured via general functional scales, the pattern and progression of acute dysphagia following reperfusion therapies is less known. To determine the progression of acute dysphagia (0-72 h) following reperfusion therapies and relationships between various stroke parameters and dysphagia, twenty-six patients were prospectively recruited across two EVT and thrombolysis centres in Brisbane, Australia. Dysphagia was screened via the Gugging Swallowing Screen (GUSS) at the bedside at three timepoints: 0-24 h, 24-48 h, and 48-72 h post-reperfusion therapies. Across three groups (EVT only, thrombolysis only, or both), the incidence of any dysphagia within the first 24 h of reperfusion therapy was 92.31% (n = 24/26), 91.30% (n = 21/23) by 48 h, and 90.91% (n = 20/22) by 72 h. Fifteen patients presented with severe dysphagia at 0-24 h, 10 at 24-48 h, and 10 at 48-72 h. Whilst dysphagia was not significantly correlated to infarct penumbra/core size, dysphagia severity was significantly related to the number of passes required during EVT (p = 0.009).Dysphagia continues to persist in the acute stroke population despite recent advancements in technology aimed to reduce morbidity and mortality post-stroke. Further research is required to establish protocols for management of dysphagia post-reperfusion therapies.

Downregulation of Nrp1 transcription promotes blood-brain barrier disruption following experimental cerebral ischemia-reperfusion.

Disruption of the blood-brain barrier (BBB) following cerebral ischemia-reperfusion injury (CIRI) is a major factor in the pathophysiology of stroke. Endothelial cell-cell communication is essential for maintaining BBB integrity. By analyzing GSE227651 data, we found that a decrease in endothelial cell-cell communication mediated by Sema3/Nrp1 may be due to the downregulation of Nrp1 transcription, which could contribute to BBB breakdown after CIRI. We confirmed this hypothesis by using western blot analysis to show a reduction in Nrp1 protein levels in penumbra endothelial cells after CIRI in mice. We then overexpressed Nrp1 specifically in brain endothelial cells using adeno-associated virus in mice. Furthermore, Nrp1 overexpression had a protective effect on BBB integrity, as evidenced by a decrease in IgG and albumin leakage caused by CIRI in mice. Finally, we found that Nrp1 overexpression also reduced brain cell death and neurological deficits induced by cerebral ischemia-reperfusion in mice. Our findings suggest that Nrp1 downregulation may be a key factor in the breakdown of endothelial cell-cell communication and subsequent BBB disruption following CIRI. Targeting Nrp1-mediated pathways may be a promising approach for mitigating BBB damage and alleviating neurological consequences in stroke patients.

Comparison of amiodarone and esmolol for prevention of reperfusion ventricular fibrillation in individuals undergoing heart valve or aortic surgery: a study protocol for a randomized controlled clinical trial.

BACKGROUND: Amiodarone and esmolol can help to prevent and treat post-cardiac surgery reperfusion ventricular fibrillation. However, the relative efficacies of these two drugs remain unknown. The aim of the current trial is to compare the performances of amiodarone and esmolol for preventing reperfusion ventricular fibrillation following open heart surgery. METHODS/DESIGN: This is a single-center, prospective, double-blind, controlled clinical trial. A total of 260 patients undergoing heart valve or aortic surgery will be assigned randomly to treatment with prophylactic esmolol (intervention group) or amiodarone (control group). The main outcome is the incidence of reperfusion ventricular fibrillation following aortic opening during extracorporeal circulation. The secondary outcomes are the rate of automatic cardiac resuscitation, energy and frequency of electrical defibrillation, number of electrical defibrillations, and pacemaker use in the two groups of patients. Information on the patients' general condition and the durations of anesthesia, extracorporeal circulation, aortic occlusion, and operation time will be recorded. We will also compare the heart rate, mean arterial pressure, and central venous pressure between the two groups of patients at induction of anesthesia (T1), start of surgery (T2), start of extracorporeal circulation (T3), aortic block (T4), aortic opening (T5), after opening for 10 (T6), 20 (T7), and 30 min (T8), at cessation of extracorporeal circulation (T9), and at the end of surgery (T10) and compare blood gas analysis results at T1, T5, T9, and T10. DISCUSSION: This study will determine if prophylactic esmolol is more effective than amiodarone for reducing the incidence of reperfusion ventricular fibrillation in patients undergoing heart valve or aortic surgery. TRIAL REGISTRATION: China Clinical Trials Registry ChiCTR1900026429. Registered on 2019.10.9.

Ischemia-Reperfusion Increases TRPM7 Expression in Mouse Retinas.

Ischemia is the main cause of cell death in retinal diseases such as vascular occlusions, diabetic retinopathy, glaucoma, or retinopathy of prematurity. Although excitotoxicity is considered the primary mechanism of cell death during an ischemic event, antagonists of glutamatergic receptors have been unsuccessful in clinical trials with patients suffering ischemia or stroke. Our main purpose was to analyze if the transient receptor potential channel 7 (TRPM7) could contribute to retinal dysfunction in retinal pathologies associated with ischemia. By using an experimental model of acute retinal ischemia, we analyzed the changes in retinal function by electroretinography and the changes in retinal morphology by optical coherence tomography (OCT) and OCT-angiography (OCTA). Immunohistochemistry was performed to assess the pattern of TRPM7 and its expression level in the retina. Our results show that ischemia elicited a decrease in retinal responsiveness to light stimuli along with reactive gliosis and a significant increase in the expression of TRPM7 in Müller cells. TRPM7 could emerge as a new drug target to be explored in retinal pathologies associated with ischemia.

Emergent use of ticagrelor during endovascular reperfusion in large arterial occlusions.

OBJECTIVE: Given many emerging indications for endovascular interventions in ischemic strokes, a safe and effective adjuvant antiplatelet regimen for acute revascularization has become a subject of interest. Ticagrelor is a direct oral P2Y12 inhibitor that may achieve rapid platelet suppression than standard oral therapies. We report our experience of Ticagrelor use in revascularization of acute large arterial steno-occlusive disease, describing procedural post-procedure thrombotic events, major hemorrhages, and other clinical outcomes. METHODS: This was a single-center retrospective case series of large steno-occlusive disease requiring endovascular reperfusion with emergent adjuvant Ticagrelor, defined as 30 min of the procedure from skin puncture to closure of the arteriotomy. Major outcomes investigated were thromboembolism in the target artery, and symptomatic intracranial or extracranial major hemorrhages. Additional analyses were performed with respect to timing of the administration and use of rescue GPIIb/IIIa inhibitors if any. RESULTS: 73 consecutive patients were identified, presenting with severe ischemic stroke (median NIHSS 16) of large artery origin. 67% required stent placement (45% cervical carotid, 22% intracranial artery), 9.5% angioplasty and 23% mechanical thrombectomy only. Two experienced symptomatic in-stent occlusion, and 7 experienced major hemorrhages (9.5%) including 3 fatal symptomatic intracranial hemorrhages (4.1%). Among 19 subjects (26%) who received pretreatment with Ticagrelor, there were fewer GPIIb/IIIa administration, angioplasty and stenting, without yielding benefit in functional outcome or mortality. GPIIb/IIIa was administered as rescue therapy in 45 subjects (62%), which was found associated with increased bleeding compared to patients receiving Ticagrelor only, in whom no bleeding complications were recorded (16% vs. 0%; p = 0.03). CONCLUSION: We report our findings on Ticagrelor as an adjuvant antiplatelet therapy in ischemic stroke of large arterial origin requiring emergent revascularization. Effectiveness, safety, need for additional rescue treatment, and comparison to other commonly used oral antiplatelets should be investigated in future prospective studies.

The Protective Pathways Activated in Kidneys of αMUPA Transgenic Mice Following Ischemia\Reperfusion-Induced Acute Kidney Injury.

Despite the high prevalence of acute kidney injury (AKI), the therapeutic approaches for AKI are disappointing. This deficiency stems from the poor understanding of the pathogenesis of AKI. Recent studies demonstrate that αMUPA, alpha murine urokinase-type plasminogen activator (uPA) transgenic mice, display a cardioprotective pathway following myocardial ischemia. We hypothesize that these mice also possess protective renal pathways. Male and female αMUPA mice and their wild type were subjected to 30 min of bilateral ischemic AKI. Blood samples and kidneys were harvested 48 h following AKI for biomarkers of kidney function, renal injury, inflammatory response, and intracellular pathways sensing or responding to AKI. αMUPA mice, especially females, exhibited attenuated renal damage in response to AKI, as was evident from lower SCr and BUN, normal renal histology, and attenuated expression of NGAL and KIM-1. Notably, αMUPA females did not show a significant change in renal inflammatory and fibrotic markers following AKI as compared with wild-type (WT) mice and αMUPA males. Moreover, αMUPA female mice exhibited the lowest levels of renal apoptotic and autophagy markers during normal conditions and following AKI. αMUPA mice, especially the females, showed remarkable expression of PGC1α and eNOS following AKI. Furthermore, MUPA mice showed a significant elevation in renal leptin expression before and following AKI. Pretreatment of αMUPA with leptin-neutralizing antibodies prior to AKI abolished their resistance to AKI. Collectively, the kidneys of αMUPA mice, especially those of females, are less susceptible to ischemic I/R injury compared to WT mice, and this is due to nephroprotective actions mediated by the upregulation of leptin, eNOS, ACE2, and PGC1α along with impaired inflammatory, fibrotic, and autophagy processes.

Single-cell analysis reveals the immune heterogeneity and interactions in lungs undergoing hepatic ischemia-reperfusion.

Hepatic ischemia-reperfusion IR (HIR) is an unavoidable pathophysiological process during liver transplantation, resulting in systematic sterile inflammation and remote organ injury. Acute lung injury (ALI) is a serious complication after liver transplantation with high postoperative morbidity and mortality. However, the underlying mechanism is still unclear. To assess the phenotype and plasticity of various cell types in the lung tissue microenvironment after HIR at the single-cell level, single-cell RNA sequencing (scRNA-seq) was performed using the lungs from HIR-induced mice. In our results, we identified 23 cell types in the lungs after HIR and found that this highly complex ecosystem was formed by subpopulations of bone marrow-derived cells that signaled each other and mediated inflammatory responses in different states and different intervals. We described the unique transcriptional profiles of lung cell clusters and discovered two novel cell subtypes (Tspo+Endothelial cells and Vcan+ monocytes), as well as the endothelial cell-immune cell and immune cell-T cell clusters interactome. In addition, we found that S100 calcium binding protein (S100a8/a9), specifically and highly expressed in immune cell clusters of lung tissues and exhibited detrimental effects. Finally, the cellular landscape of the lung tissues after HIR was established, highlighting the heterogeneity and cellular interactions between major immune cells in HIR-induced lungs. Our findings provided new insights into the mechanisms of HIR-induced ALI and offered potential therapeutic target to prevent ALI after liver transplantation.

Neuroprotective effects of ivermectin against transient cerebral ischemia-reperfusion in rats.

Stroke is a leading cause of disability and death worldwide. Ivermectin is a broad-spectrum anti-parasitic agent with potential anti-bacterial, anti-viral, and anti-cancer effects. However, the effects of ivermectin on the brain are poorly described. This study examined the effects of ivermectin on cerebral ischemia-reperfusion (IR) in rats. A rat model of transient global IR was induced by bilateral carotid artery occlusion for 20 min. Rats received ivermectin (2 mg/kg/day, ip) one hour after inducing cerebral IR for three consecutive days at 24-h intervals. Next, we examined the effects of ivermectin on brain infarction, histopathology, malondialdehyde levels, myeloperoxidase activity, spatial learning and memory, and phospho-AMPK protein levels. The results showed that ivermectin reduced brain infarct size (P < 0.001) and histopathological changes such as cerebral leukocyte accumulation and edema (P < 0.05) compared to untreated rats with IR. Treatment with ivermectin also decreased myeloperoxidase activity (P < 0.01) and malondialdehyde levels (P < 0.05) while increasing AMPK activity (P < 0.001), memory, and learning compared to the untreated IR group. Overall, we show for the first time that ivermectin conferred neuroprotective effects in a rat model of cerebral IR. Our results indicate that three days of treatment with ivermectin reduced brain infarct size, lipid peroxidation, and myeloperoxidase activity and improved memory and learning in rats with cerebral IR. These effects likely occurred via AMPK-dependent mechanisms.

Intravenous tirofiban following successful reperfusion in intracranial large artery atherosclerotic stroke: A secondary analysis of a randomized clinical trial.

OBJECTIVE: This study aimed to investigate whether treatment with adjunct intravenous tirofiban is associated with improved outcomes following successful reperfusion in patients with intracranial atherosclerotic stroke. METHODS: Patients with intracranial large artery atherosclerotic (LAA) stroke and an expanded Treatment in Cerebral Ischemia angiographic score of 2b50 to 3 from the Effect of Intravenous Tirofiban versus Placebo Before Endovascular Thrombectomy on Functional Outcomes in Large Vessel Occlusion Stroke (RESCUE BT) trial were included. The primary outcome was the difference in proportion of independent functional outcome (modified Rankin score of 0-2 at 90 days). Safety outcomes included the rates of symptomatic intracranial hemorrhage (sICH) and 90-day mortality. RESULTS: Among the 382 patients with intracranial LAA stroke and successful reperfusion, 175 patients (45.8%) were treated with intravenous tirofiban and 207 (54.2%) with placebo. The proportion of patients with independent functional outcome at 90 days was 54.3% (95 out of 175) with tirofiban and 44.0% (91 out of 207) with placebo (adjusted odds ratio [aOR], 1.58; 95% CI, 1.02-2.44; p = 0.04). Intravenous tirofiban was not significantly associated with an increased risk of sICH (12/175 [6.9%] vs. 11/207 [5.3%]; aOR, 1.41; 95% CI, 0.59-3.34; p = 0.44) or 90-day mortality (21/175 [12.0%] vs. 34/207 [16.4%]; aOR, 0.71; 95% CI, 0.38-1.31; p = 0.27). INTERPRETATION: Among patients with acute intracranial LAA stroke and successful reperfusion following endovascular thrombectomy, adjunct intravenous tirofiban was associated with a higher rate of independent functional outcome, without higher rates of sICH or mortality. Confirmatory randomized trials in these patients are desirable.

Artesunate alleviates intestinal ischemia/reperfusion induced acute lung injury via up-regulating AKT and HO-1 signal pathway in mice.

Acute Lung injury (ALI) is a common complication following intestinal ischemia/reperfusion (II/R) injury that can lead to acute respiratory distress syndrome (ARDS) a fatal illness for there is no specific therapy. The semisynthetic artemisinin Artesunate (Art) extracted from Artemisia annua has been found lots of pharmaceutical effects such as anti-malaria, anti-inflammatory, and anti-apoptosis. This study aimed to investigate the effect of Artesunate on intestinal ischemia/reperfusion and the mechanism of how Artesunate works in mice. To establish the II/R model, the C57BL/c mice were subjected to occlude superior mesenteric artery (SMA) for 45 min and 120 min reperfusion, and the lung tissue was collected for examination. Severe lung injury occurred during the II/R, meanwhile Art pretreatment decreased the lung injury score, wet/dry ratio, the level of MDA, MPO, IL-1ß, TNFα, CXCL1, MCP-1, the TUNEL-positive cells, Bax and Cleaved-Caspase3 protein expression obviously, and increased the activity of SOD and the expression of Bcl-2. In addition, the protein of P-AKT and HO-1 were upregulated during the Art pretreatment. Then the AKT inhibitor Triciribin and HO-1 inhibitor Tin-protoporphyrin IX were administered which reversed the protein expression of apoptosis, AKT and HO-1. Our study suggests that Art mitigated the II/R induced acute lung injury by targeting the oxidative stress, inflammatory response and apoptosis which is associated with the activating of AKT and HO-1, providing novel insights into the therapeutic candidate for the treatment of II/R induced acute lung injury.

Chitosan oligosaccharide attenuates acute kidney injury and renal interstitial fibrosis induced by ischemia-reperfusion.

Acute kidney injury (AKI) and renal interstitial fibrosis are global clinical syndromes associated with high morbidity and mortality. Renal ischemia-reperfusion (I/R) injury, which commonly occurs during surgery, is one of the major causes of AKI. Nevertheless, an efficient therapeutic approach for AKI and the development of renal interstitial fibrosis is still lacking due to its elusive pathogenetic mechanism. Here, we showed that chitosan oligosaccharide (COS), a natural oligomer polysaccharide degraded from chitosan, significantly attenuates I/R-induced AKI and maintains glomerular filtration function by inhibiting oxidative stress, mitochondrial damage, and excessive endoplasmic reticulum stress both in vitro and in vivo. In addition, long-term administration of COS can also attenuate the proliferation of myofibroblasts, mitigate extra cellular matrix deposition, and thus inhibit the transition of AKI to chronic kidney disease through participating in metabolic and redox biological processes. Our findings provide novel insights into the protective role of COS against acute kidney injury.

Could retrograde reperfusion combined with washout technique broaden the applicability of marginal grafts in liver transplantation? Intra-operative and short-term outcomes of a prospective cohort.

INTRODUCTION: many revascularization techniques were designed to reduce the imbalance of ischemia-reperfusion injury. This study's objective is to evaluate retrograde reperfusion (RR) compared to sequential anterograde reperfusion (AR), with and without the washout technique (WO). METHOD: this prospective cohort study collected data from 94 deceased donor orthotopic liver transplants and divided it into three groups: RR with WO (RR+WO), AP with WO (AR+WO), and AP without WO (AR). This study did not assign the reperfusion technique to the participants. The primary outcome considered the early graft dysfunction, and secondary outcomes included post-reperfusion syndrome (PRS), post-reperfusion lactate, surgery fluid balance, and vasoactive drug dose during the surgery. RESULTS: 87 patients were submitted to the final analysis-29 in the RR+WO group, 27 in the AR+WO group, and 31 in the AR group. Marginal grafts prevalence was not significantly different between the groups (34% vs. 22% vs. 23%; p=0.49) and early graft dysfunction occurred at the same rate (24% vs. 26% vs. 19%; p=0.72). RR+WO reduced serum post-reperfusion lactate (p=0.034) and the incidence of significant PRS (17% vs. 33% vs. 55%; p=0.051), but norepinephrine dosing >0.5mcg/kg/min were not different during the surgery (20,7% vs. 29,6% vs. 35,5%, p=0.45). CONCLUSIONS: primary outcome was not significantly different between the groups; however, intraoperative hemodynamic management was safer using the RR+WO technique. We theorized that the RR+WO technique could reduce the incidence of PRS and benefit marginal graft survival following diseased donor orthotopic liver transplantation.