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INTRODUCTION: First pass effect (FPE), achievement of complete recanalization (mTICI 2c/3) with a single pass, is a significant predictor of favorable outcomes for endovascular treatment (EVT) in large vessel occlusion stroke (LVO). However, data concerning the impact on functional outcomes and predictors of FPE in medium vessel occlusions (MeVO) are scarce. PATIENTS AND METHODS: We conducted an international retrospective study on MeVO cases. Multivariable logistic modeling was used to establish independent predictors of FPE. Clinical and safety outcomes were compared between the two study groups (FPE vs non-FPE) using logistic regression models. Good outcome was defined as modified Rankin Scale 0-2 at 3 months. RESULTS: Eight hundred thirty-six patients with a final mTICI ⩾ 2b were included in this analysis. FPE was observed in 302 patients (36.1%). In multivariable analysis, hypertension (aOR 1.55, 95% CI 1.10-2.20) and lower baseline NIHSS score (aOR 0.95, 95% CI 0.93-0.97) were independently associated with an FPE. Good outcomes were more common in the FPE versus non-FPE group (72.8% vs 52.8%), and FPE was independently associated with favorable outcome (aOR 2.20, 95% CI 1.59-3.05). 90-day mortality and intracranial hemorrhage (ICH) were significantly lower in the FPE group, 0.43 (95% CI, 0.25-0.72) and 0.55 (95% CI, 0.39-0.77), respectively. CONCLUSION: Over 2/3 of patients with MeVOs and FPE in our cohort had a favorable outcome at 90 days. FPE is independently associated with favorable outcomes, it may reduce the risk of any intracranial hemorrhage, and 3-month mortality.

Currently, the incision design for periodontal and implant surgeries is mainly based on the surgeon's personal preference. The primary aim of this study is to review the intricate periodontal microvascular system and to illustrate the potential impact of commonly applied flap designs on the integrity of this system. A complete literature electronic search resulted in 37 relevant articles. The maxillary, facial, and lingual arteries supply the microvasculature system, including the supraperiosteal, intraligamental, and intraosseous arterioles. These arterioles have their own territories yet are extensively interconnected. The impact of common papilla management techniques are discussed, including tunneling; papilla base, incision, and preservation; and flap-releasing incisions. Flap design can impact reperfusion and blood inflow in the early healing phase, which eventually influences wound closure probability, healing speed, surgical predictability, tissue volume change, and postoperative morbidity. Future studies on the three-dimensional distribution of microvasculature and clinical impact of various flap designs on tissue reperfusion can lead to evidence-based incision selection and improved wound-healing outcomes. [ABSTRACT FROM AUTHOR]

• CircRNA_0003307 enhanced angiogenesis, invasion, and migration in BMECs under OGD. • CircRNA_0003307 acts as a sponge for miRNA-191-5p, preventing its binding to CDK6. • CircRNA_0003307 enhanced BMEC angiogenesis by targeting the miR-191-5p/CDK6. • CircRNA_0003307 ameliorated cerebral injury in the I/R-injured mice. The role of miR-191-5p in cerebral ischemia–reperfusion (I/R) injury has been established, with its expression in endothelial cells demonstrating anti-angiogenic effects. A potential circular RNA, circRNA_0003307, has been identified through bioinformatics analysis as a candidate for interaction with miR-191-5p, yet its functional significance in brain I/R injury remains unexplored. We aimed to investigate whether circRNA_0003307 regulates brain microvascular endothelial cell (BMEC) vascular tube formation, invasion, and migration by regulating the miR-191-5p cascade. Mouse BMECs (bEnd.3) were cultured and exposed to oxygen-glucose deprivation (OGD). The effects of circRNA_0003307 on vessel-like tube formation and cellular migration were examined. In addition, we investigated the protective effects of circRNA_0003307 on I/R injury in mice. The results showed the level of circRNA_0003307 was concentration-dependently increased in OGD-induced bEnd.3 cells. ODG-induction enhanced angiogenesis, migration, and invasion of bEnd.3 cells, which were further promoted by the transfection of pcDNA-0003307. Silencing circRNA_0003307 expression showed the opposite results. The dual luciferase assay demonstrated miRNA-191-5p interacted with circRNA_00033073′ UTR, and miRNA-191-5p could bind with CDK6. Meanwhile, circRNA_0003307 promoted the expression of CDK6 by sponging miRNA-191-5p. The overexpression of circRNA_0003307 activated the angiogenesis, migration, and invasion of OGD-induced bEnd.3 cells, which were hindered by miRNA-191-5p mimic or siRNA-CDK6. Thus, circRNA_0003307 promoted ODG-induced angiogenesis, migration, and invasion of bEnd.3 cells by targeting miR-191-5p/CDK6 axis. In vivo, circRNA_0003307 had protective effects on brain I/R injury, including neuroprotection, anti-apoptosis and angiogenesis. CircRNA_0003307 may be a promising therapeutic target for the treatment of cerebral I/R injury. [ABSTRACT FROM AUTHOR]

Uremic Encephalopathy results from the elevation of toxins and blood-brain barrier (BBB) disruption. Renal Ischemia/Reperfusion (I/R) injury is the principal cause of acute kidney injury and brain tissue injury. The present study was crafted to estimate the restorative impact of platelet-rich plasma (PRP) and exosome injection before the reperfusion phase on the kidney following renal I/R injury and its influence on brain tissue by tracking the histopathological, biochemical, and Doppler ultrasonography alternations in both kidney and brain tissue. Forty mature male rats were divided into five groups as follows: control, I/R, PRP, exosome, and Exosome + PRP. Renal Doppler ultrasonography was traced for all rats. Serum kidney functions and acetylcholine esterase enzyme (AchE) were evaluated. Both Gamma-aminobutyric acid (GABA) and glutamate were assessed in brain tissues. The oxidative stress (malondialdehyde), anti-oxidative (glutathione and catalase), and pro-inflammatory (Tumor necrosis factor- α and interleukin-6) markers were estimated in renal tissues. Additionally, morphometric histological examination was performed in both renal and brain tissues. Both PRP and exosome-received rats exhibited a significant improvement in both serum kidney functions and AchE compared to I/R rats. There was a 3.39-fold increase in GABA and a 2.27-fold decrease in glutamate levels in the brain tissue of PRP rats compared to the I/R rats. A significant elevation (P ≤ 0.0001) of glutathione and catalase besides a significant reduction in the expression of TNF-α and IL-6 was observed in renal tissue compared to I/R rats. A significant severe reduction (P < 0.0001) in the number of Purkinje cells, pyramidal cells in the cerebellar cortex, and the CA1 region in the hippocampus was observed in I/R rats which was significantly alleviated by both PRP and exosome. Furthermore, there was a significant improvement in Doppler parameters. PRP exerted a significant superior impact on the restoration of kidney functions and repairing uremic-induced damage in brain tissue. [ABSTRACT FROM AUTHOR]

Despite the widespread adoption of emergency coronary reperfusion therapy, reperfusion‐induced myocardial injury remains a challenging issue in clinical practice. Following myocardial reperfusion, S100A8/A9 molecules are considered pivotal in initiating and regulating tissue inflammatory damage. Effectively reducing the S100A8/A9 level in ischemic myocardial tissue holds significant therapeutic value in salvaging damaged myocardium. In this study, HA (hemagglutinin)‐ and RAGE (receptor for advanced glycation end products)‐ comodified macrophage membrane‐coated siRNA nanoparticles (MMM/RNA NPs) with siRNA targeting S100A9 (S100A9‐siRNA) are successfully prepared. This nanocarrier system is able to target effectively the injured myocardium in an inflammatory environment while evading digestive damage by lysosomes. In vivo, migration of MMM/RNA NPs to myocardial injury lesions is confirmed in a myocardial ischemia‐reperfusion injury (MIRI) mouse model. Intravenous injection of MMM/RNA NPs significantly reduced S100A9 levels in serum and myocardial tissues, further decreasing myocardial infarction area and improving cardiac function. Targeted reduction of S100A8/A9 by genetically modified macrophage membrane‐coated nanoparticles may represent a new therapeutic intervention for MIRI. [ABSTRACT FROM AUTHOR]

Methods Results Interpretation Endovascular thrombectomy (EVT) was shown to be safe and efficacious in patients with large core stroke in multiple randomized controlled trials. However, the impact of reperfusion and other procedural metrics on EVT outcomes in this population has not been well‐characterized.From the SELECT2 trial, we evaluated the association between reperfusion status, first‐pass effect (near‐complete or complete reperfusion [extended thrombolysis in cerebral infarction (eTICI) 2c‐3] in 1 pass), procedure time and primary technique (aspiration vs stent‐retriever) with functional outcomes in patients receiving EVT across ASPECTS (3 vs 4 vs 5) and core estimate strata (<70 vs ≥70ml, <100 vs ≥100ml, and <150 vs ≥150ml).Of 180 patients who received thrombectomy, 144 (80%) achieved successful reperfusion (eTICI 2b‐3) and demonstrated better clinical outcomes (adjusted generalized odds ratios [aGenOR]: 1.48, 95% confidence interval [CI]: 1.01–2.15), compared with unsuccessful reperfusion. Results were consistent across ASPECTS and core estimate strata. Additionally, complete or near‐complete reperfusion (eTICI 2c‐3) was associated with better functional outcome (aGenOR: 1.99, 95% CI: 1.33–2.97) in patients achieving successful reperfusion. Functional outcome point estimates favored those with first‐pass‐effect (42 of 167 (25%), aGenOR: 1.46, 95% CI: 0.96–2.24). Longer procedure time was associated with worse modified Rankin scale (mRS) distribution (aGenOR: 0.92, 95% CI: 0.87–0.96, p‐value = 0.001 for 10 minutes increment). Aspiration‐first technique was used in 43 of 154 (25%) patients and was not associated with higher reperfusion (88% vs 78%, p = 0.18) or better functional outcome (aGenOR: 0.74, 95% CI: 0.50–1.10) as compared with stent‐retriever first.Successful reperfusion resulted in improved clinical outcomes in large core patients across baseline ischemic core strata. Near complete or complete reperfusion was further associated with better outcomes, whereas prolonged procedures were associated with worse outcomes. Results were consistent regardless of the technique used. ANN NEUROL 2024 [ABSTRACT FROM AUTHOR]

Decompensated cirrhotic patients experience severely increased intestinal permeability and bacterial translocation. Thus, autologous blood salvaged during deceased donor liver transplantation (DDLT) may be contaminated with enteric bacteria. We aimed to evaluate bacterial contamination of autologous blood salvaged during DDLT and its association with post-transplant bacteremia. In 30 patients undergoing DDLT, bacterial culture was performed in salvaged autologous blood samples: one before graft reperfusion (non-leukoreduced) and two after graft reperfusion (non-leukoreduced and leukoreduced). The primary outcome was bacterial contamination of salvaged autologous blood. Seven of 30 patients (23.3%) were positive for bacteria (3 enteric/4 non-enteric) before graft reperfusion while 11 patients (36.7%) were positive (5 enteric/6 non-enteric) after graft reperfusion. Six of 7 patients who were positive for bacteria before graft reperfusion were positive after graft reperfusion with the same bacteria. Only 4 of 11 contaminated blood samples were converted to negative after leukoreduction. Post-transplant bacteremia risk was insignificantly greater in patients who received autologous blood with bacteria than in patients without bacteria (30.0% vs. 5.0%, P = 0.06). We found contamination of salvaged autologous blood with enteric bacteria throughout DDLT and incomplete performance of leukoreduction, indicating high bacterial load. The potential association between contaminated autotransfusion and post-transplant bacteremia warrants further validation in a larger prospective study. Clinical trial notation: This study was registered at the Clinical Research Information Service (CRiS; https://cris.nih.go.kr; No. KCT0007223; principal registration investigator: Sangbin Han, date of registration: April 25, 2022). [ABSTRACT FROM AUTHOR]

Leptomeningeal collaterals (LMCs) are crucial in mitigating the impact of acute ischemic stroke (AIS) by providing alternate blood flow routes when primary arteries are obstructed. This article explores the evolutionary pathophysiology of LMCs, highlighting their critical function in stroke and the genetic and molecular mechanisms governing their development and remodelling. We address the translational challenges of applying animal model findings to human clinical scenarios, emphasizing the need for further research to validate emerging therapies—such as pharmacological agents, gene therapy and mechanical interventions—in clinical settings, aimed at enhancing collateral perfusion. Computational modelling emerges as a promising method for integrating experimental data, which requires precise parameterization and empirical validation. We introduce the ‘Evolucollateral Dynamics’ hypothesis, proposing a novel framework that incorporates evolutionary biology principles into therapeutic strategies, offering new perspectives on enhancing collateral circulation. This hypothesis emphasizes the role of genetic predispositions and environmental influences on collateral circulation, which may impact therapeutic strategies and optimize treatment outcomes. Future research must incorporate human clinical data to create robust treatment protocols, thereby maximizing the therapeutic potential of LMCs and improving outcomes for stroke patients. [ABSTRACT FROM AUTHOR]

Reactive oxygen species generated via reperfusion cause lipid damage and induce lipid peroxidation, leading to cerebral ischemia/reperfusion injury and exacerbation of cerebral infarction. Lipid radicals are key molecules generated during lipid peroxidation. Therefore, understanding the spatiotemporal behavior of lipid radicals is important to improve the therapeutic outcomes of cerebral infarction. However, the behaviors of lipid radicals in the brain remain unclear. In this study, we aimed to evaluate the distribution of radioactivity in a transient middle cerebral artery occlusion (tMCAO) model using lipid radical detection probe [125I] 1 to assess the behaviors of lipid radicals after cerebral ischemia/reperfusion. The tMCAO model administered [125I] 1 exhibited significant differences in the timing and location of radioactivity accumulation between the ischemic and non-ischemic regions. Liquid chromatography/mass spectrometry analysis identified the lipid radical adducts formed by the reaction of 1 with the lipid radicals generated after reperfusion. More adducts were detected in the ischemic region samples than in the non-ischemic region samples. Therefore, 1 successfully detected the lipid radicals generated after cerebral ischemia/reperfusion. Overall, this study demonstrates the potential of nuclear medical imaging using radiolabeled 1 to detect the lipid radicals generated after cerebral ischemia/reperfusion. Our approach can aid in the development of new therapeutic agents scavenging lipid radicals after cerebral reperfusion by facilitating the determination of therapeutic efficacy and optimal administration period. [Display omitted] • Radioiodinated probe detects lipid radicals after cerebral ischemia-reperfusion. • Ex vivo ARG maps lipid radical distribution post-ischemia. • Lipid radical generation varies in timing and location across brain regions. • LC/MS identifies lipid radical adducts at different timepoints after reperfusion. • Edaravone's effectiveness in suppressing lipid radicals evaluated spatiotemporally. [ABSTRACT FROM AUTHOR]

Revascularization procedures such as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) are crucial to restore blood flow to the heart and are used in the treatment of myocardial infarction (MI). However, these techniques are known to cause myocardial reperfusion injury in the ischemic heart. The present study aims to mimic ischemia–reperfusion injury in vitro on primary human cardiomyocytes (HCMs) and use the established injury model to study the rescue mechanism of skeletal muscle cell (SkM)-seeded electrospun fiber-coated human amniotic membrane scaffold (EF–HAM) on injured cardiomyocytes through paracrine secretion. An in vitro ischemia–reperfusion injury model was established by exposing the HCM to 5 h of hypoxia, followed by a 6 h reoxygenation period. Six different conditioned media (CM) including three derived from SkM-seeded EF–HAMs were introduced to the injured cells to investigate the cardioprotective effect of the CM. Cell survival analysis, caspase-3 and XIAP expression profiling, mitochondrial membrane potential analysis, and measurement of reactive oxygen species (ROS) were conducted to evaluate the outcomes of the study. The results revealed a significant increase in the viability of HCM exposed to H/R injury by 77.2% (p < 0.01), 111.8% (p < 0.001), 68.7% (p < 0.05), and 69.5% (p < 0.05) when supplemented with HAM CM, EF–HAM 3 min CM, EF–HAM 5 min CM, and EF–HAM 7 min CM, respectively. Furthermore, CM derived from SkM-seeded EF–HAM scaffolds positively impacted hypoxia-/reoxygenation-induced changes in caspase-3 expression, mitochondrial membrane potential, and reactive oxygen species generation, but not in XIAP expression. These findings suggest that EF–HAM composite scaffolds can exert antiapoptotic and cardioregenerative effects on primary human cardiomyocytes through the paracrine mechanism. [ABSTRACT FROM AUTHOR]

Postmenopausal cardiovascular health is a critical determinant of longevity. Consumption of beetroot juice (BR) and other nitrate-rich foods is a safe, effective non-pharmaceutical intervention to increase systemic bioavailability of the vasoprotective molecule, nitric oxide, through the exogenous nitrate (NO3−)–nitrite (NO2−)–nitric oxide (NO) pathway. We hypothesized that a single dose of nitrate-rich beetroot juice (BRnitrate 600 mg NO3−/140 mL, BRplacebo ∼ 0 mg/140 mL) would improve resting endothelial function and resistance to ischemia–reperfusion (IR) injury to a greater extent in early-postmenopausal (1–6 years following their final menstrual period (FMP), n = 12) compared to late-postmenopausal (6+ years after FMP, n = 12) women. Analyses with general linear models revealed a significant (p < 0.05) time*treatment interaction effect for brachial artery adjusted flow-mediated dilation (FMD). Pairwise comparisons revealed that adjusted FMD was significantly lower following IR-injury in comparison to all other time points with BRplacebo (early FMD 2.51 ± 1.18%, late FMD 1.30 ± 1.10, p < 0.001) and was lower than post-IR with BRnitrate (early FMD 3.84 ± 1.21%, late FMD 3.21 ± 1.13%, p = 0.014). A single dose of BRnitrate significantly increased resting macrovascular function in the late postmenopausal group only (p = 0.005). Considering the postmenopausal stage-dependent variations in endothelial responsiveness to dietary nitrate, we predict differing mechanisms underpin macrovascular protection against IR injury. [ABSTRACT FROM AUTHOR]

Objective(s): Myocardial arrhythmia is a major complication of ischemia-reperfusion (I/R) injury in patients with diabetes. Irisin has significant cardioprotective effects, while its role in the pathophysiology of I/R injury-induced myocardial arrhythmia in the presence of diabetes is not well identified. Here, we aimed to investigate the potential antiarrhythmic impacts and mechanisms (mitochondrial biogenesis, endoplasmic reticulum (ER) stress, and pyroptosis) by which irisin reduces I/R injury-induced myocardial arrhythmia in diabetic rats. Materials and Methods: Thirty high-fat diet-induced diabetic rats were subjected to I/R injury and myocardial arrhythmia. Irisin (0.5 µg/kg/day) was injected intraperitoneally before induction of I/R injury. Electrocardiography was used to measure the incidence and severity of ventricular arrhythmias. ELISA and western blotting analyses were employed to quantify the expression of mitochondrial biogenesis, ER stress, and pyroptosis-related proteins in ischemic myocardium. Results: Irisin treatment in diabetic rats significantly decreased the lactate dehydrogenase level and the number and severity of arrhythmia induced by I/R injury. Irisin up-regulated the expression of mitochondrial biogenesis-related proteins while down-regulating the expression of ER stress and pyroptosis-related proteins. Furthermore, the inhibition of mitochondrial quality control by mdivi-1 significantly abolished the cardioprotective effect of irisin. Conclusion: Our findings suggest that irisin reduced myocardial arrhythmia induced by I/R injury in diabetic rats by modulating the interaction of mitochondrial biogenesis and ER stress proteins and inhibiting the pyroptosis pathway. These findings provide a promising strategy for managing myocardial arrhythmia in diabetic patients, but supplementary studies are needed to confirm the clinical efficacy of irisin in these patients. [ABSTRACT FROM AUTHOR]

Introduction: Extracorporeal membrane oxygenation cannulation strategies vary between adults and children. Femoral approach is common in adults and extremity morbidity is well-documented. Aside from limb ischemia, complications in children are theorized and have yet to be studied. This study aims to comprehensively evaluate implications of pediatric femoral cannulation. Methods: This is a single-center retrospective review of children <21 years, undergoing femoral venoarterial (VA) or venovenous (VV) cannulation between 2015 and 2022. The primary outcome was incidence of lower extremity complications on ECMO (groin hematoma/hemorrhage, vascular thrombosis, North-South syndrome, compartment syndrome, limb loss). Secondary outcome was incidence of post-decannulation extremity complications (pseudoaneurysm, surgical site infection, vascular thrombosis, motor/sensory deficits). Results: 29 children were cannulated via femoral approach. Most required VA support (89%). Common sites were right femoral artery (70.8%) and right femoral vein (56%). 18 patients (75%) had distal reperfusion cannulas (DPC) placed. Short-term lower extremity complication rate was 59%, most frequently groin hematoma/hemorrhage (30%) and North-South syndrome (19%). Compartment syndrome occurred in 3 patients (11%), though none suffered digit/limb loss. There were no significant differences in complications between cannulation approach (open vs percutaneous) or vessel laterality (ipsilateral vs contralateral). Of those decannulated (n = 15), median ECMO duration was 8 days. Following decannulation, 20% suffered pseudoaneurysm. Ten (63%) experienced ipsilateral motor weakness which resolved in 50% of patients at 1-month follow-up; 20% suffered sensory deficits all resolving by discharge. Conclusion: Approximately one third of children who underwent femoral cannulation suffered groin hematoma/hemorrhage and nearly 20% experienced North-South syndrome. Following decannulation, most had extremity weakness while sensory deficits were rarer. This marked risk of extremity morbidity prompts proactive inpatient monitoring and close surveillance after discharge. [ABSTRACT FROM AUTHOR]

Myocardial infarction resulting from coronary artery atherosclerosis is the leading cause of heart failure, which represents a significant global health burden. The limitations of conventional pharmacologic thrombolysis and flow reperfusion procedures highlight the urgent need for new therapeutic strategies to effectively treat myocardial infarction. In this study, we present a novel biomimetic approach that integrates polyphenols and metal nanoenzymes, inspired by the structure of pomegranates. We developed tannic acid-coated Mn-Co 3 O 4 (MCT) nanoparticles in combination with an injectable collagen hydrogel for the effective treatment of myocardial infarction. The hydrogel enhanced the infarct microenvironment, while the slow-released MCT targets mitochondria to inhibit the post-infarction surge of reactive oxygen species, providing anti-apoptotic and anti-inflammatory effects. RNA sequencing revealed the potential of hydrogels to serve as an interventional mechanism during the post-infarction inflammatory phase. Notably, we found that the hydrogel, when combined with the nanopomegranate-based therapy, significantly improves adverse ventricular remodeling and restores cardiac function in early infarction management. The MCT hydrogel leverages the unique benefits of both MCT nanopomegranates and collagen, demonstrating a synergistic effect. This approach provides a promising example of the potential cooperation between nanomimetic structures and natural biomaterials in therapeutic applications. [Display omitted] • Developed novel pomegranate-inspired MCT nanoparticles combined with collagen hydrogel for MI therapy. • Efficacious in attenuating the inflammatory response, safeguarding cardiomyocytes and preserving their contractile function. • The MCT hydrogel can effectively alleviate the post-infarction inflammatory response and improve the long-term prognosis in MI rats. • Biomimetic MCT hydrogels offer a potential therapy for myocardial infarction. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the differences in endovascular thrombectomy (EVT) outcomes of patients treated for acute ischaemic stroke (AIS) during business versus off-business hours. Methods: A single-centre retrospective cohort study of patients with AIS treated with EVT from February 1, 2015, to May 31, 2021, was performed at a comprehensive stroke centre (CSC). Patients were divided into business (Monday to Friday, 8 AM-5 PM) versus off-business hours groups. The primary outcome was functional neurological disability, scored using the modified Rankin Scale (mRS) at 90 days. Secondary outcomes included the rate of successful reperfusion and procedural workflow time delays. Differences in proportions were assessed using Fisher's exact and Chi-Square tests as appropriate. For continuous variables, differences in medians between groups were assessed using Mann-Whitney U tests. Results: A total of 676 patients were included, with 399 patients (59%) comprising the off-business-hour group. No significant differences were seen in age, sex, ASPECTS score, or NIHSS at arrival. Off-business hours strokes had a longer delay between CSC arrival to groin puncture (minutes: 81 vs 44, P <.0001) and between imaging to groin puncture (minutes: 67 vs 32, P <.0001) compared to the business hours strokes. There were no differences in the rate of successful reperfusion (mTICI ≥2b) between groups (82% vs 83%, P =.61). At 90 days, 65% of patients in both groups had an mRS ≤2 (P =.91). Conclusion: Despite workflow delays in initiating EVT during off-business hours, there were no differences in the rate of successful reperfusion or functional outcomes. [ABSTRACT FROM AUTHOR]

Background: Renal ischemia-reperfusion injury (IRI) is a significant contributor to renal dysfunction, acute kidney injury (AKI), and associated morbidity and mortality. Resveratrol, a polyphenol and phytoalexin, is known for its anti-inflammatory, antioxidant, and anti-cancer properties. This study investigates the nephroprotective potential of resveratrol in a rat model of renal IRI. Materials and methods: Twenty-eight male Sprague-Dawley rats were divided into four groups: Sham, IRI, DMSO, and Resveratrol. The Sham group underwent identical procedures without renal pedicle clamping, while the IRI group experienced 30 min of ischemia followed by 2 h of reperfusion. The DMSO group received dimethyl sulfoxide (DMSO) intraperitoneally 30 min before ischemia, and the Resveratrol group received 30 mg/kg resveratrol intraperitoneally 30 min before ischemia. Biochemical parameters (Urea, creatinine, IL-1β, NF-κβ, SOD, GSH, Bcl-2, and caspase-3) and histopathological changes were assessed. Results: IRI caused a substantial increase in serum creatinine, Urea, IL-1β, NF-κβ, and caspase-3 levels, while simultaneously decreasing SOD, GSH, and Bcl-2 levels. Resveratrol treatment mitigated these effects by lowering inflammatory and apoptotic markers, enhancing antioxidant defenses, and improving histological outcomes. Conclusion: Resveratrol demonstrates significant nephroprotective effects in renal IRI, primarily through its antioxidant, anti-inflammatory, and anti-apoptotic properties. [ABSTRACT FROM AUTHOR]

Background: The role of histone methyltransferase SETDB1 in renal ischemia–reperfusion (I/R) injury has not been explored yet. This study aims to investigate the potential mechanism of SETDB1 in regulating renal I/R injury and its impact on mitochondrial damage and oxidative stress. Methods: The in vivo model of renal I/R in mice and the in vitro model of hypoxia/reoxygenation (H/R) in human renal tubular epithelial cells (HK-2) were constructed to detect the expression of SETDB1. Next, the specific inhibitor (R,R)-59 and knockdown viruses were used to inhibit SETDB1 and verify its effects on mitochondrial damage and oxidative stress. Chromatin immunoprecipitation (ChIP) and coimmunoprecipitation (CoIP) were implemented to explore the in-depth mechanism of SETDB1 regulating renal I/R injury. Results: The study found that SETDB1 had a regulatory role in mitochondrial damage and oxidative stress during renal I/R injury. Notably, SESN2 was identified as a target of SETDB1, and its expression was under the influence of SETDB1. Besides, SESN2 mediated the regulation of SETDB1 on renal I/R injury. Through deeper mechanistic studies, we uncovered that SETDB1 collaborates with heterochromatin HP1β, facilitating the labeling of H3K9me3 on the SESN2 promoter and impeding SESN2 expression. Conclusions: The SETDB1/HP1β-SESN2 axis emerges as a potential therapeutic strategy for mitigating renal I/R injury. [ABSTRACT FROM AUTHOR]

Emergency computed tomography (CT) often does not allow for comprehensive coronary artery assessment. However, CT may reveal pathological myocardial hypoperfusion suggestive of acute myocardial infarction (AMI), especially in patients presenting with a different diagnostic hypothesis. CT hypoperfusion is known to be associated with myocardial infarction, however the diagnostic value of CT hypoperfusion for the detection of AMI is still not well evaluated. This was a single-centre retrospective study including patients who underwent invasive coronary angiography (ICA) due to suspected AMI based on incidental perfusion defects upon emergency CT imaging between 2018 and 2023. A total of 22 patients (mean age 66.3 ± 10.8 years, 11 female) were included in this analysis. The diagnosis of AMI was established in all cases leading to ICA. Culprit coronary artery lesions with an indication of percutaneous coronary intervention were detected in all patients who underwent ICA. Spearmann correlation for hypoperfused segments on CT imaging and the corresponding vascular territory upon ICA was significantly substantial (ρ = 0.73, p = < 0.001). The higher the number of affected myocardial segments, the faster ICA was initiated. Mean time between the suspicion of AMI on CT imaging and ICA was 196 (29–4044) minutes. Myocardial hypoperfusion on emergency CT imaging should be considered as AMI until proven otherwise, independent of the clinical scenario leading to performance of CT imaging and whether imaging was performed for the exclusion of non-cardiac pathologies. Early initiation of further diagnostic workup may potentially avoid delays to invasive treatment and reduce the CT-to-catheter-time. Our study explicitly underlines that myocardial hypoperfusion upon contrast enhanced CT imaging needs to be considered as sign of acute myocardial infarction and indicates targeted clinical workup to rule out this diagnosis and to shorten the timeframe from imaging diagnosis to interventional treatment. [ABSTRACT FROM AUTHOR]

Background/Objectives: To propose criteria for retreating previously embolized PAVMs and determining the effectiveness of the criteria to prevent paradoxical embolization. Methods: A retrospective review of patients with PAVMs treated at a single HHT center of excellence between 1 January 2013, and 10 September 2023, was performed. Patients with PAVM recurrence were either retreated or observed based on the following criteria for PAVM reintervention: 1. Embolic device(s) not creating a sufficiently dense matrix, such that a channel through them may be >/ 2 mm; 2. Accessory feeding artery or pulmonary collateral >/ 2 mm; 3. Hemoptysis in a patient with no other explanation. Results: A total of 438 PAVMs were treated in 151 patients, including 106 patients with definite, 14 possible, and 31 doubtful HHT. Post-embolization PAVM recurrence occurred in 36 patients (36/151, 23.8%), including 15 patients (15/151, 9.9%) with 22 PAVMs (22/438, 5.0%) meeting criteria for reintervention. A total of 21 patients (21/151, 13.9%) with recurrence did not meet reintervention criteria and were therefore observed. Pre-treatment paradoxical embolization occurred in 36 patients (36/151) for a lifetime prevalence rate of 23.7%. Post-treatment paradoxical embolization did not occur in any patients following PAVM embolization (0/151). There was one case of iatrogenic paradoxical embolization in a patient being treated for systemic collateral reperfusion and hemoptysis. However, this was not included given that it was not a spontaneous event. Conclusions: Utilizing modern embolization techniques and devices, the proposed reintervention criteria, and screening intervals, paradoxical embolizations can be effectively prevented in patients with PAVMs. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the ability of pentoxifylline when compared to lovastatin and chlorpromazine as nephroprotective substances in cases of renal ischemia and reperfusion syndrome (IRI). A total of 36 adult male animals were randomly allocated into four groups (untreated control group, pentoxifylline group, lovastatin group, and chlorpromazine group), each consisting of nine animals. All groups were submitted to experimental ischemia and reperfusion procedures. The animals were evaluated 24, 72 and 120 hours after IRI, including physical examinations, serum urea and creatinine measurements, as well as histopathological, morphometric, and stereological analyses of the renal tissue. Results indicated that 24 hours after IRI, only chlorpromazine was effective in controlling azotemia. At the 72-hour mark, both chlorpromazine and pentoxifylline exhibited efficacy. After 120 hours, all three substances demonstrated renal protective qualities. Pentoxifylline was the most effective in preserving the structural integrity of kidney tissue, followed by chlorpromazine. In conclusion, all three treatments (pentoxifylline, chlorpromazine, and lovastatin) were effective. Pentoxifylline proved to be promising in the response against acute tubular necrosis, although chlorpromazine presented earlier renoprotective effects in terms of maintaining renal function. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is the sudden decrease in renal function that can be attributed to dysregulated reactive oxygen species (ROS) production and impaired mitochondrial function. Irisin, a type I membrane protein secreted by skeletal muscles in response to physical activity, has been reported to alleviate kidney damage through regulation of mitochondrial biogenesis and oxidative metabolism. In this study, a macrophage membrane‐coated metal‐organic framework (MCM@MOF) is developed as a nanocarrier for encapsulating irisin to overcome the inherent characteristics of irisin, including a short circulation time, limited kidney‐targeting ability, and low membrane permeability. The engineered irisin‐mediated biomimetic nanotherapeutics have extended circulation time and enhanced targeting capability toward injured kidneys due to the preservation of macrophage membrane proteins. The irisin‐encapsulated biomimetic nanotherapeutics effectively mitigate acute ischemia‐reperfusion injury by protecting mitochondrial function and modulating SOD2 levels in renal tubular epithelial cells. The present study provides novel insights to advance the development of irisin as a potential therapeutic approach for AKI. [ABSTRACT FROM AUTHOR]

Ischemia/reperfusion (I/R) is an important inducer of acute kidney injury (AKI), and triggers the generation of reactive oxygen species (ROS) and the expression of matrix metalloproteinase 2 (MMP2), exacerbating kidney damage. Given the immense potential of vitamin E (VitE) as a natural fat-soluble antioxidant in kidney protection, we designed the nanoparticles (NPs) that could dual respond to ROS and MMP2, aiming to accurately deliver VitE to renal injury cells. The NPs utilized Gel-SH as a sensitive receptor for MMP2 and diselenide as a sensitive receptor for ROS, while PEG2k modification enhanced biocompatibility and prevented phagocytosis mediated by the mononuclear phagocyte system. The amphiphilic Gel-SH and diselenide encapsulate the liposoluble VitE and self-assemble into the NPs with a hydrodynamic size of 69.92 nm. Both in vivo and in vitro experiments based on these NPs show good biocompatibility and the ability of target renal injury cells. In vivo kidney I/R injury models and in vitro cell hypoxia/reoxygenation models, the NPs have demonstrated effects in reducing oxidative stress and alleviating AKI. Notably, VitE can preferentially react with peroxyl radical (LOO•) than polyunsaturated fatty acid (PUFA), inhibiting the formation of carbon centered radical (L•), thereby blocking the chain reaction between PUFA and LOO• in ferroptosis. The NPs also inhibit the transition from AKI to chronic kidney disease, with few side effects. Thus, the NPs with dual-responsiveness to MMP2 and ROS for targeted delivery of VitE to renal injury cells exhibit remarkable effects in inhibiting ROS and the chain reactions of ferroptosis, making it a promising therapeutic agent against AKI caused by I/R. [ABSTRACT FROM AUTHOR]

Introduction Material and Methods Results Conclusions Uterine transplantation was developed for the treatment of absolute uterine factor infertility. As it is a new modality of transplantation, there is still room for technical improvement. A factor that impacts graft survival in organ transplantation is the warm ischemia time. In uterine transplantation specifically, at least two vascular anastomoses are performed on each side of the uterus, and the graft revascularization takes place when the vascular clamps of the arteries and veins are released on both sides simultaneously. For this reason, the warm ischemia time in uterine transplant is expected to be considerably long. The purpose of this study was to compare the sequential technique of uterine graft revascularization, which aims to reduce the warm ischemia time of the procedure, with the simultaneous revascularization technique.For the procedure, the uterine auto‐transplantation technique was performed using 10 non‐pregnant adult ewes weighing about 45 kg, divided into two groups: simultaneous revascularization group (5 animals) and sequential revascularization group (5 animals). To evaluate the groups, we analyzed the procedure and warm ischemia times, graft macroscopy, hemodynamic, laboratory, and histological parameters of the uterus.The sequential revascularization technique group had similar surgical procedure times, and the warm ischemia time was significantly shorter with medians of 32 min in the sequential group versus 72 min in the simultaneous group (p < 0.008). The graft macroscopy and hemodynamic, laboratory, and histological parameters evaluated were similar between the groups.The sequential revascularization technique proved to reduce the warm ischemia time in the sheep uterine auto‐transplantation model without compromising graft viability. [ABSTRACT FROM AUTHOR]

Retinal ischemia–reperfusion (IR) injury is a basic pathological procedure in clinic and associated with various ischemic retinal diseases, including glaucoma, diabetic retinopathy, retinal vascular occlusion, etc. The purpose of this work is to investigate the effect of ciclopirox olamine (CPX) on retinal IR injury and further explore the underlying mechanism. In vitro assay exhibited that CPX exhibited significant neuroprotection against oxygen glucose deprivation (OGD) and oxidative stress-induced injuries in 661W photoreceptor cells. OGD injury showed a proinflammatory phenotype characterized by significantly increased production of cytokines (IL-6, IL-23 and TNF-α), while CPX significantly inhibited their secretion. In addition, the in vivo experiment demonstrated that CPX significantly preserved the normal thickness of the retina. Therefore, we suggest that CPX is identified in our research as a prospective therapeutic agent for retinal IR injury. [ABSTRACT FROM AUTHOR]

Background: As a supportive treatment, the effectiveness of oxygen therapy in ischemic stroke (IS) patients remains unclear. This study aimed to evaluate the relationships between arterial partial pressure of oxygen (PaO2) and both consciousness at discharge and all-cause mortality risk in ICU IS patients. Methods: Blood gas measurements for all patients diagnosed with IS were extracted from the MIMIC-IV database. Patients were classified into four groups based on their average PaO2 during the first ICU day: hypoxemia (PaO2 < 80 mmHg), normoxemia (PaO2 80–120 mmHg), mild hyperoxemia (PaO2 121–199 mmHg), and moderate/severe hyperoxemia (PaO2 ≥ 200 mmHg). The primary endpoint was 90-day all-cause mortality. Secondary outcomes included the level of consciousness at discharge, assessed by the Glasgow Coma Scale (GCS), and 30-day all-cause mortality. Multivariate Cox regression and Restricted cubic spline (RCS) analysis were used to investigate the relationship between mean PaO2 and mortality, and to assess the nonlinear association between exposure and outcomes. Results: This study included a total of 946 IS patients. The cumulative incidence of 30-day and 90-day all-cause mortality increased with decreasing PaO2 levels. RCS analysis revealed a nonlinear relationship between PaO2 and the risk of 30-day all-cause mortality (nonlinear P < 0.0001, overall P < 0.0001), as well as a nonlinear association between PaO2 and 90-day all-cause mortality (nonlinear P < 0.0001, overall P < 0.0001). The results remained consistent after excluding the small subset of patients who received reperfusion therapy. Sensitivity analysis indicated that the favorable impact on survival tends to increase with the extended duration of elevated PaO2. Conclusions: For IS patients who do not receive reperfusion therapy or whose recanalization status is unknown, a lower PaO2 early during ICU admission is considered an independent risk factor for short-term and recent mortality. Adjusting respiratory parameters to maintain supraphysiological levels of PaO2 appears to be beneficial for survival, although this finding requires further validation through additional studies. Trial registration: Not applicable. [ABSTRACT FROM AUTHOR]

Objective To evaluate the efficacy of different interventions to the extra cranial lesions in acute ischemic stroke (AIS) due to anterior tandem lesions (TL) on reperfusion. Methods As a multi-center, cross-sectional study, AIS due to anterior TL receiving mechanical thrombectomy (MT) were retrospectively collected. Interventions to the extra-cranial stenosis were recorded. Post-procedural reperfusion was assessed using the modified thrombolysis in cerebral infarction (mTICI) score. Complete revascularization was defined as mTICI 3 and good revascularization was defined as mTICI 2b/3. The relationship between different extra-cranial intervention regimens and rate of re-vascularization was compared. Results Totally 117 patients were included with 92.3% reaching good recanalization and 63.2% reaching complete re-canalization. There was no significant difference in good re-canalization rates among various extra-cranial intervention regimens. The rate of complete re-canalization was significantly higher in patients receiving endovascular therapy (P＜0.05) and there was significant difference among various endovascular treatment regimens (P＜0.01): acute balloon angioplasty only group presented the highest rate of complete re-canalization (100.0%), followed by acute stenting only group (80%), acute stenting + balloon angioplasty group (73.7%) and conservative treatment group (54.3%). Conclusions Endovascular intervention to extra-cranial stenosis contributes to complete re-canalization in AIS due to anterior TL receiving MT, and acute balloon angioplasty seems to be quite effective than acute stenting. [ABSTRACT FROM AUTHOR]

Cerebral ischemia can lead to destruction of the blood—brain barrier (BBB), the main cause of cerebral edema and cerebral infarction. BBB damage is also one of the key factors affecting the result of drug therapy. We studied the protective effect of 5-day pretreatment with protocatechuic aldehyde (PAL) at doses of 10 and 20 mg/kg on BBB function and structure after middle cerebral artery occlusion/reperfusion (MCAO/R) in rats. The infarct volume, behavioral neurological deficit score, and Evans blue content in the brain were estimated. We also evaluated the content of nitric oxide (NO) and activities of inducible and neuronal NO synthases. Expression of aquaporin-4 (AQP-4), occludin, claudin-5, and MMP-3 in the brain tissues was estimated by Western blotting. The BBB ultrastructure was analyzed under an electron microscope. We revealed that PAL at both used doses significantly reduced the neurological deficit score, brain infarct volume, and Evans blue extravasation. Electron microscopy showed that PAL significantly improved the ultrastructure of BBB and alleviated its injury. Pretreatment with PAL increased expression of occludin and claudin-5 and reduced expression of AQP-4 and MMP-3. At the same time, the release of NO and activities of NO synthases were notably inhibited. Our results suggest that PAL can be a promising compound to attenuate cerebral ischemia resulting from occlusion/reperfusion injury via BBB protection. [ABSTRACT FROM AUTHOR]

Objectives: Liver ischemia-reperfusion (I/R) is the director's origin of damages in various clinical situations, especially surgery and transplantation. Inflammatory damages are critical because of the chronicity of I/R injuries (I/RI). The hepatoprotective and antiinflammatory properties of silibinin have been reported in different studies. This study aimed to investigate the effect of Silibinin on the expression of the pannexin-1 (Panx1) gene during hepatic I/R. Materials and Methods: In this case-control animal study, a total of 32 male Wistar rats (n=8 in each) were surveyed. The animals were randomly assigned into four equal groups as follows: Group 1 (Control): the rats underwent a midline laparotomy with normal saline injection; Group 2 (SILI): the rats received Silibinin (50 mg/kg) after laparotomy; Group 3 (I/R): the rats underwent I/R surgery and received normal saline; and Group 4 (I/R+SILI): the rats received silibinin before ischemia and directly following reperfusion. Blood and liver tissue samples were taken after three hours of reperfusion aftermath 1-hour ischemia to evaluate histological changes, gene expression, and serum markers of hepatic injury. Results: While the serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the I/R group significantly increased compared to the control group (P < 0.001), they significantly decreased in the SILI+I/R group (P < 0.001). Silibinin ameliorated inflammatory impairments of liver tissue, such as neutrophil and macrophage infiltration and activation, hepatocyte degeneration and vacuolation, hepatic vascular endothelial damage, and sinusoid proliferation in the I/R group. The expression of the Panx1 mRNA during I/R significantly increased compared to the control group (P < 0.001), but silibinin reduced the expression (P < 0.001). Conclusions: We witnessed that silibinin reduced liver tissue damages during hepatic I/R. Correcting the expression of the Panx1 gene during I/R is probably one of the mechanisms of anti-inflammatory effects of silibinin. [ABSTRACT FROM AUTHOR]

Purpose: To determine the impact of time profile of tirofiban hydrochloride administration on short-term outcomes in patients with acute myocardial infarction (AMI) undergoing emergency percutaneous coronary intervention (PCI). Methods: A total of 112 patients with AMI who received PCI treatment in The First People's Hospital of Tianshui, Tianshui, China were randomly and equally assigned to study and control groups. The study group received intravenous tirofiban hydrochloride bolus (10 µg/kg) 1 - 2 h before PCI, followed by sustained infusion at 0.15 µg/kg/min for 36 h after the procedure. Control group received the same regimen immediately after PCI. Myocardial injury markers, cardiac functional parameters, ST-segment resolution, myocardial perfusion changes, bleeding complications, and adverse cardiovascular events over 6 months were evaluated. Results: When compared with control group, the study group exhibited significantly lower cardiac troponin T (cTnT) levels and lower serum creatine kinase-MB (CK-MB) levels at 7 days post-PCI (p < 0.05). Furthermore, the study group showed significantly reduced left ventricular end-diastolic diameter (LVEDD), and left ventricular end-systolic diameter (LVESD), along with higher left ventricular ejection fraction (LVEF) after 7 days (p < 0.05). The study group also exhibited superior ST-segment resolution and significant improvement in myocardial perfusion 90 min post-treatment and significantly lower incidence of reperfusion arrhythmias (p < 0.05). Both groups had similar rates of minor bleeding events and no incidence of severe complications or fatalities. Conclusions: Administering tirofiban preoperatively enhances coronary blood flow, improves myocardial perfusion, and reduces the risk of distal embolic events without increasing severe bleeding complications. Larger-scale, multicenter studies with longer follow-up periods are required to confirm these findings and evaluate the safety and efficacy of different administration time for tirofiban infusion in patients with AMI undergoing PCI. [ABSTRACT FROM AUTHOR]

Introduction: The University of Wisconsin (UW) and histidine-tryptophan-ketoglutarate (HTK) are the most popular organ-preservative solutions. Ultrastructure of organelles reflects the functionality of cells, but less is understood about ultrastructural changes of hepatocytes after machine perfusion (MP) with HTK, than with UW solution. Methods: We evaluated the ultrastructure of hepatocytes preserved in HTK solution during hypothermic (4°C) and midthermic (22°C) MP (HMP and MMP, respectively) temperatures using osmium maceration scanning electron microscopy. Results: The functional ultrastructure of mitochondria in hepatocytes was maintained immediately after HMP and MMP. After 2 h in a porcine isolated liver reperfusion model (IRM) that simulates transplanted liver grafts, mitochondrial cristae became denser and some large vacuoles that we assumed were autophagosomes were detected in hepatocytes after HMP. Autophagy functions in the suppression of reactive oxygen generation and subsequent apoptosis, and these findings indicated that HMP is more effective than MMP when livers are preserved in HTK solution. Conclusion: The present findings contradict the previous findings of the UW solution that MMP is more effective than HMP. Thus, various combinations of conditions for MP should be carefully optimized before changing preservatives. [ABSTRACT FROM AUTHOR]

Background: Hypothermic Oxygenated machine PErfusion (HOPE) can reduce ischemic reperfusion injury and improve outcomes for liver transplant recipients. However, the effect of HOPE on high‐risk extended criteria donor (ECD) and donation after circulatory death determination (DCDD) grafts is incomplete, despite the expectation that this cohort benefit maximally from HOPE. Accordingly, this paper aims to characterize the effect of HOPE on ECD and DCDD grafts. Methods: This study includes all papers comparing HOPE to static cold storage for high‐risk ECD and DCDD grafts. Systematic searches of Medline, Embase, and Scopus were completed using the terms "HOPE" OR "hypothermic oxygenated machine perfusion" AND "liver transplantation". Data were extracted and analyzed using IBM SPSS to perform the meta‐analysis. Results: A total of 2286 records were identified, with 10 meeting the inclusion criteria. Overall, the quality of evidence is heterogenous with many papers relying on retrospective controls. However, pooled analysis demonstrates HOPE to significantly reduce the rate of early allograft dysfunction, 12‐month graft failure, re‐transplantation, total biliary complications, and non‐anastomotic strictures for high‐risk grafts. Conclusions: There is good evidence that HOPE improves outcomes following liver transplantation across a number of biochemical and clinical endpoints for high‐risk grafts. Of note, the reduction in biliary complications and re‐transplantation is particularly significant given the morbidity associated with these endpoints. However, further, high‐quality prospective trials with contemporary controls and clinically relevant primary endpoints are needed to better define the impact of HOPE for this cohort of grafts. [ABSTRACT FROM AUTHOR]

Background: Pharmacological inhibition of aryl hydrocarbon receptor (AhR) activation after ischemia alleviates cerebral ischemia/reperfusion (IR) injury. Purpose: To investigate whether AhR antagonist administration after reperfusion was also effective in attenuating cerebral IR injury. Material and Methods: A total of 24 Sprague–Dawley rats were divided into the sham-operated group (no IR), control group (IR), and 6,2′,4′-trimethoxyflavone (TMF) group (IR + TMF administration), with 10 rats assigned to each group. Cerebral IR injury was induced by 60 min of middle cerebral artery occlusion followed by reperfusion. TMF (5 mg/kg) was used as the AhR antagonist and was administered intraperitoneally immediately after reperfusion. Cerebral IR injury was observed using magnetic resonance imaging (MRI) and neurobehavioral assessments at baseline, immediately after ischemia, and at 3 days after ischemia. Results: On MRI, the TMF group showed no significant differences in relative apparent diffusion coefficient (ADC), T2, and fractional anisotropy (FA) values; midline shift value; and infarct volume. In terms of neurobehavioral function, factors such as grip strength, contralateral forelimb use, time to touch, and time to remove adhesive tape from the forepaw, were also not significantly different between the control and TMF groups. Conclusion: This study demonstrated that AhR treatment after reperfusion had no noticeable effect on reducing cerebral IR injury in rats. [ABSTRACT FROM AUTHOR]

Intravenous thrombolysis remains the most accessible and effective reperfusion therapy available to patients with acute ischaemic stroke. Treatment with intravenous thrombolysis improves the odds of favourable functional outcome with the unacceptably low risk of haemorrhagic complications. Even in the current era of endovascular thrombectomy, intravenous thrombolysis remains the backbone of acute stroke treatment due to its accessibility and relative ease of administration. Since intravenous alteplase was first approved for acute ischaemic stroke in the mid 1990s, there have been significant advances in expanding the indication and time window for treatment, in addition to transitioning towards tenecteplase use for stroke thrombolysis. In this review, we will provide a narrative on the use of thrombolysis in acute ischaemic stroke including an up-to-date discussion on recent advances in thrombolytic therapy. [ABSTRACT FROM AUTHOR]

Acute and chronic hypertension causes cerebral vasculopathy, increasing the risk of ischemia and stroke. Our study aimed to compare the effects of arterial pressure reduction on the pial microvascular responses induced by hypoperfusion and reperfusion in spontaneously hypertensive Wistar rats, desamethasone-induced hypertensive Wistar rats and age-matched normotensive Wistar rats fed for 3 months with a normal diet or normal diet supplemented with L-arginine or Taurisolo® or L-arginine plus Taurisolo®. At the end of treatments, the rats were submitted to bilateral occlusion of common carotid arteries for 30 min and reperfusion. The microvascular parameters investigated in vivo through a cranial window were: arteriolar diameter changes, permeability increase, leukocyte adhesion to venular walls and percentage of capillaries perfused. Hypoperfusion–reperfusion caused in all rats marked microvascular changes. L-arginine treatment was effective in reducing arterial blood pressure causing vasodilation but did not significantly reduce the damage induced by hypoperfusion–reperfusion. Taurisolo® treatment was less effective in reducing blood pressure but prevented microvascular damage from hypoperfusion–reperfusion. L-arginine plus Taurisolo® maintained blood pressure levels within the physiological range and protected the pial microcirculation from hypoperfusion–reperfusion-induced microvascular injuries. Therefore, the blood pressure reduction is not the only fundamental aspect to protect the cerebral circulation from hypoperfusion–reperfusion damage. [ABSTRACT FROM AUTHOR]

Oxidative stress triggered by testicular torsion and detorsion in young males could negatively impact future fertility. Using a rat animal model for testicular IRI (tIRI), we aim to study the induction of autophagy (ATG) during testicular ischemia and tIRI and the role of oxidative-stress-induced c-Jun N-terminal Kinase (JNK) as a cytoprotective mechanism. Sixty male Sprague-Dawley rats were divided into five groups: sham, ischemia only, ischemia+SP600125 (a JNK inhibitor), tIRI only, and tIRI+SP600125. The tIRI rats underwent an ischemic injury for 1 h followed by 4 h of reperfusion, while ischemic rats were subjected to 1 h of ischemia only without reperfusion. Testicular-ischemia-induced Beclin 1 and LC3B expression was associated with decreased p62/SQSTM1 expression, increased ATP and alkaline phosphatase (AP) activity, and slightly impaired spermatogenesis. SP600125 treatment improved p62 expression and reduced the levels of Beclin 1 and LC3B but did not affect ATP or AP levels. The tIRI-induced apoptosis lowered the expression of the three ATG proteins and AP activity, activated caspase 3, and caused spermatogenic arrest. SP600125-inhibited JNK during tIRI restored sham levels to all investigated parameters. This study emphasizes the regulatory role of JNK in balancing autophagy and apoptosis during testicular oxidative injuries. [ABSTRACT FROM AUTHOR]

To identify potentially transplantable organs in a pool of marginal kidneys, 33 porcine slaughterhouse kidneys were perfused for 4 h with whole blood. During the normothermic perfusion, plasma, urine, and tissue samples were taken. Several biomarkers for tubule injury, endothelial activation, and inflammatory response were evaluated for a potential correlation with macroscopic appearance, histology, and filtration activity. Generally, biomarker levels increased during perfusion. TLR-4, EDN-1, and NGAL were not associated with any classification. In contrast, a steeper increase in NAG and IL-6 in plasma correlated with a poor macroscopic appearance at 4 h, indicating a higher inflammatory response in the kidneys with worse macroscopy early on, potentially due to more damage at the tubules. Although long-term effects on the graft could not be assessed in this setting, early observation under machine perfusion with whole blood was feasible. It allowed the assessment of kidneys under conditions comparable to reperfusion. This setting could give surgeons further insight into the quality of marginal kidneys and an opportunity to pre-treat them. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is a leading cause of morbidity and mortality, and exercise-training (TRN) is known to reduce risk factors and protect the heart from ischemia and reperfusion injury. Though the cardioprotective effects of exercise are well-documented, underlying mechanisms are not well understood. This review highlights recent findings and focuses on cardiac factors with emphasis on K+ channel control of the action potential duration (APD), β-adrenergic and adenosine regulation of cardiomyocyte function, and mitochondrial Ca2+ regulation. TRN-induced prolongation and shortening of the APD at low and high activation rates, respectively, is discussed in the context of a reduced response of the sarcolemma delayed rectifier potassium channel (IK) and increased content and activation of the sarcolemma KATP channel. A proposed mechanism underlying the latter is presented, including the phosphatidylinositol-3kinase/protein kinase B pathway. TRN induced increases in cardiomyocyte contractility and the response to adrenergic agonists are discussed. The TRN-induced protection from reperfusion injury is highlighted by the increased content and activation of the sarcolemma KATP channel and the increased phosphorylated glycogen synthase kinase-3β, which aid in preventing mitochondrial Ca2+ overload and mitochondria-triggered apoptosis. Finally, a brief section is presented on the increased incidences of atrial fibrillation associated with age and in life-long exercisers. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To investigate the contemporary use of extracorporeal membrane oxygenation (ECMO) in conjunction with reperfusion strategies in high-risk pulmonary embolism (PE). DESIGN: Observational epidemiological analysis. SETTING: The U.S. Nationwide Inpatient Sample (NIS) (years 2016-2020). PATIENTS: High-risk PE hospitalizations. MEASUREMENTS AND MAIN RESULTS: Use of ECMO in conjunction with thrombolysis-based reperfusion (systemic thrombolysis or catheter-directed thrombolysis) or mechanical reperfusion (surgical embolectomy or catheter-based thrombectomy) with regards to in-hospital mortality and major bleeding. We identified high-risk PE hospitalizations in the NIS (years 2016-2020) and investigated the use of ECMO in conjunction with thrombolysis-based (systemic thrombolysis or catheter-directed thrombolysis) and mechanical (surgical embolectomy or catheter-based thrombectomy) reperfusion strategies with regards to in-hospital mortality and major bleeding. Among 122,735 hospitalizations for high-risk PE, ECMO was used in 2,805 (2.3%); stand-alone in 1.4%, thrombolysis-based reperfusion in 0.4%, and mechanical reperfusion in 0.5%. Compared with neither reperfusion nor ECMO, ECMO plus thrombolysis-based reperfusion was associated with reduced in-hospital mortality (adjusted odds ratio [aOR] 0.61; 95% CI, 0.38-0.98), whereas no difference was found with ECMO plus mechanical reperfusion (aOR 1.03; 95% CI, 0.67-1.60), and ECMO stand-alone was associated with increased in-hospital mortality (aOR 1.60; 95% CI, 1.22-2.10). In the cardiac arrest subgroup, ECMO was associated with reduced in-hospital mortality (aOR 0.71; 95% CI, 0.53-0.93). Among all patients on ECMO, thrombolysis-based reperfusion was significantly associated (aOR 0.55; 95% CI, 0.33-0.91), and mechanical reperfusion showed a trend (aOR 0.75; 95% CI, 0.47-1.19) toward reduced in-hospital mortality compared with no reperfusion, without increases in major bleeding. CONCLUSIONS: In patients with high-risk PE and refractory hemodynamic instability, ECMO may be a valuable supportive treatment in conjunction with reperfusion treatment but not as a stand-alone treatment especially for patients suffering from cardiac arrest. [ABSTRACT FROM AUTHOR]

Stroke is recognized as a leading cause of disability and mortality worldwide, posing a significant challenge, particularly in developing countries. The current study aimed to evaluate the neuroprotective effect of Ganoderic acid (GA) against focal ischemic stroke in rats. Material and methods.: Swiss Wistar rats were used for the current study. The rats were subjected to middle cerebral artery occlusion (MCAO) to simulate transient focal ischemia, followed by reperfusion. Various neurological parameters, including infarct size, neurological deficit score, brain water content, Evans blue leakage, nitric oxide (NO), inducible nitric oxide synthase (iNOS), lactate dehydrogenase (LDH), antioxidant levels, inflammatory cytokines, apoptosis markers, inflammatory parameters, and matrix metalloproteinases (MMP) levels, were estimated. Additionally, mRNA expressions were evaluated in the brain tissue. Results.: Dose dependently treatment of GA significantly (P < 0.001) suppressed the infarct size, neurological deflects score, brain water, evans blue leakage, NO, iNOS, LDH, C-X-C chemokine receptor type 4 (CXCR-4), monocyte chemoattractant protein-1 (MCP-1), S100 calcium-binding protein B (S-100β) and K+-Cl− cotransporter 1 (KCC1) positive cells. GA altered the level of oxidative stress parameters like Total antioxidant capacity (T-AOC), 8-hydroxy-2'-deoxyguanosine (8-OhdG), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH), malonaldehyde (MDA); cytokines viz., tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-1β, IL-6, IL-9, IL-10; inflammatory parameters such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), prostaglandin (PGE2), Nuclear factor kappa B (NF-κB); apoptosis parameters like B-cell leukemia/lymphoma 2 protein (Bcl-2), Bcl-2-associated protein x (Bax), Caspase-3; matrix metallopeptidase (MMP) parameters like MMP-2, MMP-3, and MMP-9, respectively. GA remarkably suppressed the mRNA expression of TRL-4, Syndecan-1, CSF, Aquaporin-1, OCT3, and RFX1. Conclusion.: Ganoderic acid exhibited the protection against the cerebral ischemia reperfusion via multiple mechanism. [ABSTRACT FROM AUTHOR]

Background and purpose: The aim of this study is to investigate the efficacy and safety of preoperative versus intraoperative tirofiban in patients with large vessel occlusion (LVO) due to large artery atherosclerosis (LAA). Methods: This is a retrospective multicenter cohort study based on the RESCUE‐RE (Registration Study for Critical Care of Acute Ischemic Stroke After Recanalization) trial enrolling patients with anterior circulation LVO classified as LAA within 24 h of onset. Patients were divided into three groups: preoperative tirofiban (PT), intraoperative tirofiban (IT), and no tirofiban (NT). Propensity score matching (PSM) was used to balance baseline characteristics. The efficacy outcomes included 90‐day functional independence (modified Rankin Scale score = 0–2) and early partial recanalization (EPR; defined as a modified Thrombolysis in Cerebral Infarction score = 1–2a). The safety outcomes included symptomatic intracranial hemorrhage (sICH). Results: A total of 104 matched triplets were obtained through PSM. Compared with NT, PT increased 90‐day functional independence (60.8% vs. 42.3%, p = 0.008) and EPR (42.7% vs. 18.3%, p < 0.001) rate, with a tendency to increase the asymptomatic intracranial hemorrhage (aICH) proportion (28.8% vs. 18.3%, p = 0.072). Compared with IT, PT had a higher 90‐day functional independence (60.8% vs. 45.2%, p = 0.025) and EPR (42.7% vs. 20.2%, p = 0.001) rate, with no significant difference in sICH (14.4% vs. 7.7%, p = 0.122) and aICH (28.8% vs. 21.2%, p = 0.200). Compared with NT, IT had a lower 90‐day mortality rate (9.6% vs. 24.0%, p = 0.005). Conclusions: Tirofiban shows good adjuvant therapy potential in acute ischemic stroke–LVO due to LAA patients. PT is associated with higher rates of EPR and better therapeutic efficacy. In addition, EPR may be a potential way to improve prognosis. [ABSTRACT FROM AUTHOR]

Background: Endovascular thrombectomy (EVT) and intravenous thrombolysis (IVT) have an unclear benefit in those with pre-stroke dementia or cognitive impairment, as these patients were often excluded from landmark stroke trials. We performed a systematic review and meta-analysis to assess the outcomes of IVT and EVT in these populations. Aims: Our systematic review, conforming to the Meta-Analysis of Observational Studies in Epidemiology guidelines, investigated studies on acute ischemic stroke patients with pre-stroke dementia or cognitive impairment treated with IVT or EVT. Primary outcome was favorable 90-day outcome (mRS 0–2). Secondary outcomes included 90-day mortality, symptomatic intracranial hemorrhage (SICH), and radiographic intracranial hemorrhage (ICH). Summary of review: Nine articles were identified, with five observational studies of IVT use in patients with (n = 1078) and without dementia (n = 2805) being selected for the meta-analysis. There were no significant differences in favorable outcome (adjusted OR: 0.61, 95% CI 0.24–1.59), mortality (unadjusted OR: 1.19, 95% CI 0.86–1.64), ICH (unadjusted OR: 1.32, 95% CI 0.79–2.19), and symptomatic ICH (unadjusted OR: 0.94, 95% CI 0.70–1.25) for patients undergoing IVT with pre-stroke dementia versus those without. One EVT study (n = 615 with dementia vs n = 9600 without) found no significant differences in outcomes apart from an increased odds of ICH for those with pre-existing dementia (adjusted OR: 1.57, 95% CI 1.03–2.40). A pooled analysis of three IVT studies showed no significant association of cognitive impairment (n = 93 vs n = 211 without) with all assessed outcomes, whereas a study of EVT found that pre-stroke cognitive impairment was associated with poor 90-day outcomes (mRS 3–6). Conclusion: These results suggest no substantial safety issues in the use of IVT or EVT for patients with pre-existing dementia or cognitive impairment compared to those without. However, the efficacy of these therapies in this demographic remains uncertain. Further rigorous studies that include a more nuanced outcome measurement approach are warranted. Registration: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42021240499. [ABSTRACT FROM AUTHOR]

Mild hyperbaric oxygen therapy (mHBOT) is an adjuvant therapy used in conditions where tissue oxygenation is reduced and is implemented using pressures less than 1.5 ATA and 100% O2 (instead of the classical HBOT at 1.9–3 ATA) which results in cheaper, easier to implement, and equally effective. mHBOT is offered for wellness and beauty and as an anti-aging strategy, in spite of the absence of studies on the cardiovascular system. Consequently, we investigated the impact of mHBOT on the cardiovascular system. Mechanical and energetic parameters of isolated heart submitted to ischemia/reperfusion injury and arterial contractile response from mHBOT-exposed rats were evaluated. In the heart, mHBOT increased pre-ischemic velocity of contraction and ischemic end-diastolic pressure and developed pressure and contractile economy during reperfusion. mHBOT decreased infarct size and increased the plasma nitrite levels. In the artery, mHBOT increased acetylcholine sensitivity. mHBOT protects the heart during ischemia/reperfusion and affects vascular relaxation. [ABSTRACT FROM AUTHOR]

Nitroglycerin has been of considerable interest as a treatment for ischaemic stroke. Recent clinical trials with nitroglycerin transdermal patches during the acute phase of stroke failed to improve functional outcomes. Systematic review and meta-analysis of the effectiveness of nitroglycerin in preclinical models of ischaemic stroke has not previously been reported, despite several clinical trials. To conduct a systematic review and meta-analysis of preclinical evidence regarding the effect of nitroglycerin on infarct volume in animal models of ischaemic stroke. The protocol was registered in PROSPERO (CRD42023432644). Our search identified 238 publications. Three publications met inclusion criteria (including 10 comparisons of infarct size). Study quality was modest (median 6 out of 9), with no evidence of publication bias. Nitroglycerin did not significantly reduce infarct volume (NMD point estimate 20.2 % reduction, 95 % CI −1.52–52.7 %, p = 0.068). Subgroup analysis suggested greater efficacy of nitroglycerin with direct intracarotid administration to the ischaemic territory at the time of reperfusion. A small number of studies (three) were included in this review. Overall, nitroglycerin did not reduce infarct volume in experimental stroke models. However, nitroglycerin may be of benefit when administered directly into the ischaemic territory. Given nitroglycerin's short half-life, we propose this route may minimise harmful reduction of cerebral perfusion pressure resulting from hypotension following systemic administration. • Three publications met pre-specified inclusion criteria, with no evidence of publication bias. • Nitrolgycerin did not improve stroke outcome. • The route of nitroglycerin administration accounted for a significant amount of variability between studies. • Intra-arterial administration of nitroglycerin at the time of reperfusion improves stroke outcome independent of changes in cerebral blood flow. • Nitroglycerin may be of benefit when administered directly into the ischaemic territory. [ABSTRACT FROM AUTHOR]

Ischemic Preconditioning (IPC) is a relatively new and non-invasive method involving the application of limited blood flow and its subsequent reperfusion in a specific body organ, such as the hand or leg, using a cuff pressure device. The main goal of this method is to prepare the body to cope with more severe ischemic injuries that may occur in the future. Although, IPC has gathered significant attention in clinical settings, its effects on aerobic, resistance, and speed performance and underlying mechanisms remain unclear and contradictory. Therefore, the aim of this comprehensive review article is to examine the impact of IPC on aerobic, resistance, and speed performance. Studies investigating the effects of IPC on various aspects of sports performance were included in this analysis. Relevant scientific articles were extensively searched by two researchers using databases such as PubMed, SID, Magiran, and Google Scholar. The selected keywords for the search included ischemic preconditioning, aerobic, strength, and speed performance. The inclusion criteria for the selected studies involved human subjects, publication in reputable scientific or peer-reviewed journals, and evaluation of the desired variables in these studies. A total of 15 studies were examined in this review. The diversity of exercise protocols, target body parts, intensity, and other known and unknown factors were evaluated in the findings section. Overall, the effectiveness of IPC on sports performance variables indicated its positive impact on aerobic, strength, and speed performance. These positive adaptations are created through various signaling pathways, including neural, humoral, and intercellular mechanisms. These processes play a significant role in how our body respond to stimuli such as ischemic preconditioning. It seems that ischemic preconditioning has an effective impact on sports performance. However, considering the limited and conflicting current research on its effects, further studies in this area are necessary. [ABSTRACT FROM AUTHOR]

Background: The detailed mechanisms underlying the development of ischemia‐type biliary lesions (ITBLs) in aged donor grafts remain unclear. In the present study we aimed to investigate the impact of aging on the response of the peribiliary gland (PBG) to ischemia–reperfusion injury (IRI) and its temporal changes. Methods: Experiments were performed using a 90‐min partial warm liver ischemia model in male Wistar rats of two age groups: young (7–8 weeks old) and old (52–60 weeks old). Liver tissues were obtained 24, 72, and 168 h after IRI. Histopathological and immunohistochemical assessments of the perihilar bile duct (PHBD), including the PBG, distal to the clip‐clamped site were performed. Results: Young rats showed little change in the bile duct tissues after IRI. However, old rats showed an increased PBG volume in the PHBD and marked PBG cell proliferation 24 h after IRI. Bile duct wall thickening with narrowing of the lumen peaked 72 h after IRI. Mucus production and oxidative stress in the PBG were significantly higher in old than in young rats after IRI. These findings showed a trend toward improvement 168 h after IRI. Conclusion: Age‐dependent differences in the response of the PBG to IRI may be related to differences in ITBL frequency. [ABSTRACT FROM AUTHOR]

The near-infrared spectroscopy (NIRS) vascular occlusion test (VOT) assesses microvascular reperfusion. Two strategies have been used to quantify reperfusion following reactive hyperemia, but it is unclear whether both yield similar results when comparing biological sex. This study aimed to determine whether sex differences in NIRS-based microvascular reperfusion are similarly apparent using the 10-s reactive hyperemia slope of the tissue saturation index (StO2) signal (slope 2) and the halftime to maximal reperfusion (T ½). Healthy, recreationally active males (n = 31) and females (n = 31) between 18 and 82 years took part in this study. A NIRS VOT was performed on the tibialis anterior muscle, and reperfusion was quantified using slope 2 (% s−1) and T ½ (s). Adipose tissue thickness (ATT) was higher in females (P = 0.009), which was associated with a lower StO2 (P = 0.001) and oxygenated hemoglobin (O2Hb) (P = 0.05) signal range. The StO2 slope 2 was significantly steeper in males versus females (P = 0.001) but not after correcting for ATT (P = 0.295). There were no sex differences in StO2 T ½ (P = 0.067) or O2Hb T ½ (P = 0.197). In a subset of males (n = 26) and females (n = 21) with similar ATT, there were no sex differences in StO2 slope 2 (P = 0.068), StO2 T ½ (P = 0.491), or O2Hb T ½ (P = 0.899). An ATT-corrected StO2 slope 2 or the T ½ approach is recommended for analysis of NIRS-based microvascular reperfusion when differences in ATT are present between sexes. NEW & NOTEWORTHY: Sex differences in near-infrared spectroscopy (NIRS)-based microvascular reperfusion have been previously reported. We found that greater adipose tissue thickness in females reduces kinetic measures of NIRS-based microvascular reperfusion. Sex differences are eliminated when performing an adipose tissue thickness correction, when the NIRS signal range is accounted for, or when adipose tissue thickness is similar between sexes. This highlights the importance of considering factors that affect NIRS signals, such as adipose tissue thickness, when drawing comparisons between groups. [ABSTRACT FROM AUTHOR]

Background We assessed the influence of prior nonvitamin K antagonist (NOAC) use on stroke outcomes after endovascular treatment (EVT) in patients at a high risk of stroke based on their pre-stroke CHA2DS2-VASc score, and compared them with those who did not use any antithrombotic (NAU) or antiplatelet (APT) agents. Methods Data were collected from a multicenter database comprising consecutive acute ischemic stroke patients who underwent EVT during a span of 103 months. We evaluated pre-stroke CHA2DS2-VASc scores in enrolled patients and measured instances of successful reperfusion and symptomatic hemorrhagic transformation (SHT) following EVT as the main outcome measures. Results Among 12 807 patients with acute ischemic stroke, 3765 (29.4%) had a history of atrial fibrillation. Of these, 418 patients with CHA2DS2-VASc scores ≥2 received EVT alone. The prior NOAC group showed higher successful reperfusion rates compared with the prior NAU and APT groups (p=0.04). Multivariate analysis revealed that prior NOAC use increased the likelihood of successful reperfusion after EVT (OR [95% CI] 2.54 [1.34 to 4.83], p=0.004) and improved stroke outcomes, while the prior APT group did not. Furthermore, the prior NOAC use group was not associated with SHT after EVT. Propensity score matching confirmed these findings. Conclusion Prior use of NOAC is associated with improved outcomes in high-risk stroke patients (pre-stroke CHA2DS2-VASc score ≥2) undergoing EVT. [ABSTRACT FROM AUTHOR]

Oleuropein (OLP) is a naturally occurring phenolic compound in olive plant with antioxidant and anti-inflammatory potential and can possibly be used in treating pancreatic injuries. This investigation aimed to follow the molecular mechanism behind the potential therapeutic effect of OLP against pancreatic injury persuaded by ischemia–reperfusion (I/R). Pancreatic I/R injury was induced by splenic artery occlusion for 60 min followed by reperfusion. Oral administration of OLP (10 and 20 mg/kg) for 2 days significantly alleviated I/R-persuaded oxidative damage and inflammatory responses in pancreatic tissue as indicated by the decreased malondialdehyde (MDA) content and increased glutathione peroxidase (GPx) activity, accompanied by the suppression of myeloperoxidase (MPO) activity and reduced levels of interleukin-1beta (IL-1β), nuclear factor kappa B (NF-κB), and tumor necrosis factor alpha (TNF-α) in pancreatic tissues. Furthermore, OLP treatment markedly restored the serum levels of amylase, trypsinogen-activated peptide (TAP), and lipase, with concurrent improvement in pancreatic histopathological alterations. Moreover, treatment with OLP regulated the pancreatic expression of inducible nitric oxide synthase (iNOS) and high-mobility group box 1 (HMGB1) relative to rats of the pancreatic IR group. Thus, OLP treatment significantly alleviates the I/R-induced pancreatic injury by inhibiting oxidative stress and inflammation in rats through downregulation of HMGB1 and its downstream NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

This article presents a study on the use of urinary guanidino compounds (GCs) and ureido compounds (UCs) as biomarkers for cardiac surgery-associated acute kidney injury (CSA-AKI). The study utilized a benzylic rearrangement reaction and high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to analyze the concentrations of GCs/UCs in urine samples from patients with CSA-AKI at different stages. The findings suggest that certain GC/UC metabolites show significant changes in concentration during CSA-AKI and could potentially serve as biomarkers for different stages of AKI. This research provides valuable resources and new therapeutic targets for further study on CSA-AKI. [Extracted from the article]

Background and Purpose: Thrombo‐inflammation is a key feature of stroke pathophysiology and provides multiple candidate drug targets. Thrombin exerts coagulation‐independent actions via protease‐activated receptors (PAR), of which PAR1 has been implicated in stroke‐associated neuroinflammation. The role of PAR4 in this context is less clear. This study examined if the selective PAR4 antagonist ML354 provides neuroprotection in experimental stroke and explored the underlying mechanisms. Experimental Approach: Mouse primary cortical neurons were exposed to oxygen–glucose deprivation (OGD) and simulated reperfusion ± ML354. For comparison, functional Ca2+‐imaging was performed upon acute stimulation with a PAR4 activating peptide or glutamate. Male mice underwent sham operation or transient middle cerebral artery occlusion (tMCAO), with ML354 or vehicle treatment beginning at recanalization. A subset of mice received a platelet‐depleting antibody. Stroke size and functional outcomes were assessed. Abundance of target genes, proteins, and cell markers was determined in cultured cells and tissues by qPCR, immunoblotting, and immunofluorescence. Key Results: Stroke up‐regulated PAR4 expression in cortical neurons in vitro and in vivo. OGD augments spontaneous and PAR4‐mediated neuronal activity; ML354 suppresses OGD‐induced neuronal excitotoxicity and apoptosis. ML354 applied in vivo after tMCAO reduced infarct size, apoptotic markers, macrophage accumulation, and interleukin‐1β expression. Platelet depletion did not affect infarct size in mice with tMCAO ± ML354. Conclusions and Implications: Selective PAR4 inhibition during reperfusion improves infarct size and neurological function after experimental stroke by blunting neuronal excitability, apoptosis, and local inflammation. PAR4 antagonists may provide additional neuroprotective benefits in patients with acute stroke beyond their canonical antiplatelet action. [ABSTRACT FROM AUTHOR]