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BACKGROUND AND PURPOSE: Acute ischemic stroke due to anterior circulation large-vessel occlusion (AIS-LVO) remains a leading cause of disability despite successful reperfusion therapies. Prolonged venous transit (PVT) has emerged as a potential prognostic imaging biomarker in AIS-LVO. We aimed to investigate whether PVT is associated with a decreased likelihood of excellent functional outcome (modified Rankin Scale [mRS] score of 0-1 at 90 days) after successful reperfusion. METHODS: In our prospectively collected, retrospectively reviewed database, we analyzed data from 104 patients with AIS-LVO who achieved successful reperfusion (modified Thrombolysis in Cerebral Infarction score of 2b/2c/3) between September 2017 and September 2022. PVT was defined as a time to maximum (Tmax) of ≥10 s in the superior sagittal sinus and/or torcula on computed tomography perfusion (CTP) imaging. Patients were categorized into PVT-positive (PVT+) and PVT-negative (PVT-) groups. The primary outcome was excellent functional recovery at 90 days. RESULTS: Of the 104 patients, 30 (29%) were PVT+. Excellent functional outcome was achieved in 38 patients (37%). PVT+ patients had a significantly lower rate of excellent recovery compared to PVT- patients (11% vs. 39%; p

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.

BACKGROUND: Flap transplantation technique is a commonly used surgical procedure for the treatment of severe tissue defects, but postoperative flap necrosis is easily triggered by ischemia-reperfusion injury. Therefore, it is still an important research topic to improve the survival rate of transplanted flaps. OBJECTIVE: To review the pathogenesis and latest treatment progress of flap ischemia-reperfusion injury. METHODS: CNKI, WanFang Database and PubMed database were searched for relevant literature published from 2014 to 2024. The search terms used were “flap, ischemia-reperfusion injury, inflammatory response, oxidative stress, Ca2+ overload, apoptosis, mesenchymal stem cells, platelet-rich plasma, signaling pathways, shock wave, pretreatment” in Chinese and English. After elimination of irrelevant literature, poor quality and obsolete literature, 77 documents were finally included for review. RESULTS AND CONCLUSION: Flap ischemia/reperfusion injury may be related to pathological factors such as inflammatory response, oxidative stress response, Ca2+ overload, and apoptosis, which can cause apoptosis of vascular endothelial cells, vascular damage and microcirculation disorders in the flap, and eventually lead to flap necrosis. Studies have found that mesenchymal stem cell transplantation, platelet-rich plasma, signaling pathway modulators, shock waves, and pretreatment can alleviate flap ischemia/reperfusion injuries from different aspects and to varying degrees, and reduce the necrosis rate and necrosis area of the grafted flap. Although there are many therapeutic methods for skin flap ischemia/reperfusion injury, a unified and effective therapeutic method has not yet been developed in the clinic, and the advantages and disadvantages of various therapeutic methods have not yet been compared. Most of the studies remain in the stage of animal experiments, rarely involving clinical observations. Therefore, a lot of research is required in the future to gradually move from animal experiments to the clinic in order to better serve the clinic. [ABSTRACT FROM AUTHOR]

At a global level, regional variation in the management of ST-elevation myocardial infarction (STEMI) is influenced by patient demographics and geography. Rural patients with STEMI are disadvantaged in reaching timely care owing to distance and limited ambulance and healthcare resources. Optimising models of STEMI care is key to overcoming the excess rural vs metropolitan cardiovascular morbidity and mortality. In this descriptive study, we compare patient characteristics and STEMI management in three Local Health Districts (LHDs) across NSW: a rural LHD (Western NSW [WNSWLHD]), a regional LHD (Hunter New England), and a metropolitan site (Sydney LHD). Data were collected from file audits conducted from 2019 to 2020 in a rural LHD with a single rural 24/7 cardiac catheter laboratory (WNSWLHD), a regional LHD with a part-time rural cardiac catheter laboratory, and a large regional 24/7 cardiac centre (Hunter New England LHD), and a metropolitan site (Sydney LHD), with two 24/7 cardiac centres. Patients with STEMI presenting in the three geographic regions were compared on demographics, differences in presentation, time to reperfusion treatment, time to percutaneous coronary intervention (PCI) centre, distances travelled, proportion of angiograms within 24 hours, and in-hospital mortality. During 2020, there were 675 recorded STEMI across the three regions. The rural site in WNSWLHD had the highest rate of STEMI per capita, with patients more likely to identify as Indigenous, less likely to call an ambulance, and more likely to present to a non–PCI hospital and to receive thrombolysis. Only 14% of these rural patients received primary PCI (PPCI), with patients presenting a median of 153 km from the PCI centre, vs 69% PPCI in the regional and 89% in metropolitan LHD. Thrombolysis was the main reperfusion treatment in WNSWLHD (76%), and the proportion of patients receiving no treatment was the same in all LHDs at 10%. The percentage of patients receiving angiography within 24 hours in the rural site was 84%. There was no substantial difference in in-hospital mortality among the three LHDs. We document large differences in the demographic profiles, use of ambulance, and access to PPCI in patients with STEMI across the three NSW centres. Current NSW health and ambulance protocols in a large, sparsely populated rural NSW LHD were able to deliver thrombolysis at the point of contact and facilitate "hot" transfer of patients with STEMI to a PCI centre. Long distances and transfer times mean that PPCI is a limited option in rural NSW, with scope for further improvement in models of care. [ABSTRACT FROM AUTHOR]

Background: Routine head computed tomography (CT) is performed 24 h post-acute stroke thrombolysis and thrombectomy, even in patients with stable or improving clinical deficits. Predicting CT results that impact management could help prioritize patients at risk and potentially reduce unnecessary imaging. Methods: In this institutional review board (IRB)-approved retrospective study, data from 1461 consecutive acute ischemic stroke patients at our Comprehensive Stroke Center (n = 8943, 2012–2022) who received intravenous thrombolysis or endovascular therapy, exhibited stable or improving 24-h exams, and underwent 24-h follow-up head CT per standard acute stroke care guidelines. CT reports 24 h post-stroke were reviewed for edema, mass effect, herniation, and hemorrhage. The primary outcome was any clinically relevant 24-h CT finding that led to changes in antithrombotic treatment or blood pressure goals, extended intensive care unit (ICU) stays or hospitalizations, neurosurgical interventions, or administration of mannitol or hypertonic saline. Multivariable logistic regression identified independent predictors of clinically meaningful CT abnormalities. A 24-h CT score was developed and cross-validated. Results: The mean age was 70 years, with 47% women. The median National Institutes of Health Stroke Scale (NIHSS) score at admission was 12 (interquartile range (IQR): 6–18). Stroke-related abnormalities on 24-h CT were present in 325 patients (22.2%), with 183 (12.5%) showing clinically relevant findings. Age, admission NIHSS, and blood glucose levels were independent predictors of clinically relevant 24-h CT findings. The final model C statistic was 0.72 (95% confidence interval (CI): 0.68–0.76) in the derivation cohort and 0.72 (95% CI: 0.67–0.75) in bootstrapping validation. The 24-h CT score was developed using these predictors: NIHSS score 5–15 (+3); NIHSS score ⩾16 (+5); age < 75 years (+1); admission glucose ⩾ 140 mg/dL (+1). The prevalence of clinically relevant CT findings was 4.3% in the low-risk group (24-h CT score ⩽ 4), 11.3% in the medium-risk group (score 5), and 21.4% in the high-risk group (score ⩾ 6). The 24-h CT score demonstrated good calibration. Conclusion: In patients undergoing thrombolysis or thrombectomy who undergo routine 24-h head CT despite remaining clinically stable or improving, only one in eight prove to have 24-h head CT findings that impact management. The 24-h CT score provides risk stratification that may improve resource utilization. Data access statement: A.S. and B.Z. have full access to the data used in the analysis in this article. Deidentified data will be shared after ethics approval if requested by other investigators for purposes of replicating the results. [ABSTRACT FROM AUTHOR]

Interleukin-34 (IL-34) was recently reported to be a new biomarker for atherosclerosis diseases, such as coronary artery disease and vascular dementia. IL-34 regulates the expression of proinflammatory cytokines (IL-17A, IL-1 and IL-6), which are classical cytokines involved in myocardial ischemia‒reperfusion (MI/R) injury. However, the exact role of IL-34 in MI/R remains unknown. In this study, a rat MI/R model was used to explore the effect of IL-34 on modulating inflammatory processes during MI/R injury. First, eighteen rats were subjected to 30 min of LAD ligation followed by 0 h, 1 h, 2 h, 4 h, 8 h or 24 h of reperfusion (n = 3 for each group). The level of IL-34 peaked at 4 h after MI/R in the ischemic myocardium. Next, ischemia for 30min and reperfusion for 4h (I/R) model was used. 24 rats were randomly divided into I/R group (n = 8), IL-34+IR group (n = 8) and IL-34+ab12+IR group (n = 8). We found that IL-34 pretreatment increased the expression of inflammatory cytokines, including high mobility group Box 1 (HMGB1), IL-17A, and IL-6; the expression of the apoptosis protein cleaved caspase-3; and the Bcl-2/Bax ratio within the ischemic myocardium. We also observed increased serum cardiac enzymes and a larger myocardial injury area. Treatment with a Janus kinase (JAK) pathway inhibitor, however, partially reduced the expression of these proteins and attenuated myocardial injury. Together, these results showed that IL-34 aggravates MI/R injury by inducing the expression of the HMGB1-IL-17A-IL-6 axis and apoptosis after MI/R, which is partially dependent on the JAK pathway. Therefore, blocking the JAK signaling pathway or inhibiting IL-34 expression might provide a new idea to reduce MI/R injury, but further researches are needed. [ABSTRACT FROM AUTHOR]

The graphic was created with BioRender.com. [Display omitted] Hepatic ischemia–reperfusion injury (HIRI) is an important cause of liver injury following liver transplantation and major resections, and neutrophils are the key effector cells in HIRI. Double-negative T regulatory cells (DNT) are increasingly recognized as having critical regulatory functions in the immune system. Whether DNT expresses distinct immunoregulatory mechanisms to modulate neutrophils, as in HIRI, remains largely unknown. In this study, we found that murine and human DNT highly expressed CD39 that protected DNT from extracellular ATP-induced apoptosis and generated adenosine in tandem with CD73, to induce high levels of neutrophil apoptosis. Furthermore, extracellular adenosine enhanced DNT survival and suppressive function by upregulating survivin and NKG2D expression via the A2AR/pAKT/FOXO1 signaling pathway. Adoptive transfer of DNT ameliorated HIRI in mice through the inhibition of neutrophils in a CD39-dependent manner. Lastly, the adoptive transfer of A2ar -/- DNT validated the importance of adenosine/A2AR signaling, in promoting DNT survival and immunomodulatory function to protect against HIRI in vivo. In conclusion, purinergic signaling is crucial for DNT homeostasis in HIRI. Augmentation of CD39 or activation of A2AR signaling in DNT may provide novel therapeutic strategies to target innate immune disorders. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is defined by the release of pro-inflammatory factors, leading to structural damage in renal tubules and subsequent tubular cell injury and death. Delivering drugs specifically to renal tubules to mitigate tubular cell damage holds potential for AKI treatment. In this work, we developed functional liposomes (LZM-PLNPs-TP) designed to bypass the glomerular filtration barrier and target tubules by leveraging the unique structural and pathological characteristics of glomeruli and tubules. LZM-PLNPs-TP, incorporating lysozyme (LZM) and cationic liposome, and carrying the anti-inflammatory and antioxidant drug Triptolide (TP), demonstrated favorable stability, efficient drug release, and good cytocompatibility in wide TP concentrations (0–100 ng/mL). These liposomes exhibited the enhanced renal accumulation, tubular retention, and cellular targeting through endocytosis by peritubular capillary endothelial cells. The administration of LZM-PLNPs-TP at a minimal TP dosage (0.01 mg/kg) demonstrated significant protection through the mitigation of oxidative stress and inflammation in ischemia/reperfusion injury (IRI) mice, while the naked TP (0.01 mg/kg) exhibited lower efficacy. Following treatment with LZM-PLNPs-TP, levels of serum creatine, blood urea nitrogen, superoxide dismutase, malondialdehyde, as well as the inflammatory cytokines IL-1β and IL-6 in renal IRI mice were found to be significantly reduced by factors of 2.9, 1.7, 0.7, 1.3, 2.1, and 1.9, respectively, compared to mice treated with TP alone. In summary, this study presents an LZM-targeted drug delivery system that synergistically enhances tubular reabsorption and cellular uptake, offering a promising strategy for AKI treatment. We have designed specialized liposomes (LZM-PLNPs-TP) with targeting capabilities towards renal tubules to enhance cellular internalization, offering a promising therapeutic strategy for AKI treatment. Our research confirms that the increased accumulation of LZM-PLNPs-TP in renal tubules is facilitated by peritubular capillary endothelial cells rather than glomerular filtration. LZM-PLNPs-TP demonstrated effective mitigation of oxidative stress, inflammation suppression, and significant improvement in kidney injury, ultimately leading to the restoration of renal function in murine models of AKI induced by ischemia/reperfusion. This study introduces LZM-targeted liposomes that enhance tubular reabsorption and cellular uptake synergistically, providing a promising therapeutic approach for AKI management. [Display omitted] [ABSTRACT FROM AUTHOR]

Background/Objectives: Leukocytes play a significant role in both acute kidney injury (AKI) and chronic kidney disease (CKD), contributing to pathogenesis and tissue damage. The process of leukocyte infiltration into the inflamed tissues is mediated by the interactions between the leukocytes and cell adhesion molecules (CAMs, i.e., E-selectin, P-selectin, and VCAM-1) present on the inner surface of the inflamed vasculature. Directly interfering with these interactions is a viable strategy to limit the extent of excessive inflammation; however, several small-molecule drug candidates failed during clinical translation. We hypothesized that a synthetic polymer presenting multiple copies of the high-affinity E-selecting binding peptide (P-Esbp) could block E-selectin-mediated functions and decrease leukocytes infiltration, thus reducing the extent of inflammatory kidney injury. Methods: P-Esbp was synthesized by conjugating E-selecting binding peptide (Esbp) to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer with reactive ester groups via aminolysis. The effects of P-Esbp treatment on kidney injury were investigated in two different models: AKI model (renal ischemia—reperfusion injury—RIRI) and CKD model (adenine-induced kidney injury). Results: We found that the mRNA levels of E-selectin were up-regulated in the kidney following acute and chronic tissue injury. P-Esbp demonstrated an extended half-life time in the bloodstream, and the polymer accumulated significantly in the liver, lungs, and kidneys within 4 h post injection. Treatment with P-Esbp suppressed the up-regulation of E-selectin in mice with RIRI and attenuated the inflammatory process. In the adenine-induced CKD model, the use of the E-selectin blocking copolymer had little impact on the progression of kidney injury, owing to the compensating function of P-selectin and VCAM-1. Conclusion: Our findings provide valuable insights into the interconnection between CAMs and compensatory mechanisms in controlling leukocyte migration in AKI and CKD. The combination of multiple CAM blockers, given simultaneously, may provide protective effects for preventing excessive leukocyte infiltration and control renal injury. [ABSTRACT FROM AUTHOR]

In 2024, significant advancements were made in clinical research on cerebrovascular diseases. Stroke researchers worldwide have actively contributed their expertise, and further refined the diagnosis, treatment, and management strategies for cerebrovascular diseases. Exciting breakthroughs have been made in the field of hemorrhagic stroke, including the treatment of subdural hematoma and primary intracerebral hemorrhage. At the same time, as a research hotspot in recent years, ischemic stroke has seen a continuous emergence of high-quality research results in various aspects such as intravenous thrombolysis, arterial thrombectomy, and secondary prevention, providing more robust evidence for clinical diagnosis and treatment. This article aims to summarize and interpret the key clinical research findings in the field of cerebrovascular diseases in 2024, providing readers with a better understanding of the current research hotspots and deeply understand their significance. [ABSTRACT FROM AUTHOR]

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. Methods: 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). Results: 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. Interpretation: 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 2025;97:175–184 [ABSTRACT FROM AUTHOR]

Objective: Paralysis subsequent to spinal cord decompression in the cervical or thoracic region is infrequent, with White Cord Syndrome (WCS) being among its several causes. Due to WCS's infrequency, there exists a paucity of high-level evidence concerning its manifestations. Our primary objective is to systematically collate all documented WCS cases, discern prevalent risk and prognostic factors, appraise available treatment modalities, and evaluate patient outcomes. Methods: A systematic review was conducted following PRISMA guidelines. The search included PubMed, Scopus, Embase, and Web of Science databases. Inclusion criteria required studies to be written in English, be case reports, and contain data on clinical features, management, and treatment outcomes. Exclusion criteria excluded meta-analyses, reviews, editorials, letters, books, studies with insufficient clinical data, and studies not in English or with unavailable full texts. Grey literature was not actively pursued due to identification challenges, potentially introducing selection bias. Two authors independently evaluated papers based on criteria. Disagreements were resolved with a third author. Additionally, the included articles' references were screened for additional relevant articles. Results: We found a total of 580 articles through our electronic search. After removing duplicates, 399 articles were screened. Out of the remaining 51 studies, 27 were included in the final quantitative analysis. The average age was 54 (3–79 years) with a male-to-female ratio of 2:1, 33% had OPLL, and Common medical histories were hypertension (30%), diabetes mellitus (20%), and previous ACDF surgery (8%). Of all Surgeries, 70% were done with a posterior approach and 30% with the anterior approach. 48% of cases used Intraoperative NeuroMonitoring(IONM), and Loss of Motor Evoked Potentials (MEP) occurred in 37% of cases. Patients received high-dose intravenous steroids. In 26% of cases, additional posterior cervical decompression was performed, and efforts were made to maintain mean arterial pressure above 85 mmHg in 37% of cases. Other medications were administered in 30% of cases. Over an average 26-week follow-up, 37% of patients had good recovery, 40% had partial recovery, and 23% showed no recovery. The average final Nurick grade was 3.2. Conclusions: WCS is a rare cause of postoperative neurological deficit following spinal cord decompression surgery. Risk factors for WCS include advanced age, extensive surgery, posterior approach for decompression, and the presence of OPLL. Treatment includes high-dose steroids, posterior cervical decompression, maintaining MAP over 85mmHg, rehabilitation, and sometimes neurotrophic drugs. Most patients can walk with or without assistance during follow-up, but around a quarter never regain neurological function. The only preoperative factor impacting outcomes is the preoperative neurological status (Nurick Grade). [ABSTRACT FROM AUTHOR]

Cardiac ischemia followed by reperfusion results in cardiac cell death, which has been attributed to an increase of mitochondrial Ca2+ concentration, resulting in activation of the mitochondrial permeability transition pore (PTP). Evaluating this hypothesis requires understanding of the mechanisms responsible for control of mitochondrial Ca2+ in physiological conditions and how they are altered during both ischemia and reperfusion. Ca2+ influx is thought to occur through the mitochondrial Ca2+ uniporter (MCU). However, with deletion of the MCU, an increase in mitochondrial Ca2+ still occurs, suggesting an alternative Ca2+ influx mechanism during ischemia. There is less certainty about the mechanisms responsible for Ca2+ efflux, with contributions from both Ca2+/H+ exchange and a Na+ -dependent Ca2+ efflux pathway. The molecular details of both mechanisms are not fully resolved. We discuss this and the contributions of both pathways to the accumulation of mitochondrial Ca2+ during ischemia and reperfusion. We further discuss the role of mitochondrial Ca2+ in activation of the PTP. [ABSTRACT FROM AUTHOR]

Background The safety and effectiveness of stent retriever use for patients with acute large vessel occlusion (LVO) due to intracranial atherosclerotic disease (ICAD) is not well established. We investigated the differences in clinical outcomes in patients with and without ICAD. Methods We analyzed the Japan Trevo Registry, a nationwide registry which enrolled patients with acute LVO who underwent endovascular therapy (EVT) using the Trevo retriever alone or in combination with an aspiration catheter. We compared the technical and clinical outcomes of EVT between the ICAD and No-ICAD groups. The primary outcome was effective reperfusion and the secondary outcome was modified Rankin scale (mRS) score 0-2 at 90 days. Safety outcomes were worsening of neurologic symptoms within 24 hours, any intracranial hemorrhage within 24 hours, vessel dissection/vessel perforation related to using the Trevo retriever and mortality at 90 days. Results A total of 835 patients (45 in the ICAD group and 790 in the No-ICAD group) were analyzed. In the ICAD group, more men (68.9% vs 50.8%, P=0.02) and a lower median National Institutes of Health Stroke Scale score at admission (11 vs 18, P<0.0001) were observed. The primary outcome was significantly more common in the No-ICAD group (92.5%) than in the ICAD group (80.0%) (adjusted odds ratio (aOR) 0.21, 95% CI 0.09 to 0.50). The proportion of patients with mRS score 0-2 at 90 days was significantly lower in the ICAD group (44.4% vs 42.4%, aOR 0.49, 95% CI 0.23 to 1.00, P=0.0496). Other secondary and safety outcomes were not significantly different between the two groups. Conclusions Patients with LVO with ICAD had a lower rate of effective reperfusion than those with No-ICAD. [ABSTRACT FROM AUTHOR]

Background Women with anterior circulation large vessel occlusion (LVO) have been reported to have worse outcomes after endovascular treatment (EVT) than men. Whether these disparities also exist in LVO of the posterior circulation is yet uncertain. We assessed sex differences in clinical, technical, and safety outcomes of EVT in posterior circulation LVO. Methods We used data of patients with posterior circulation LVO included in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry (2014-2018). Primary outcome was the modified Rankin Scale (mRS) score at 90 days assessed with multivariable ordinal regression analysis. Secondary outcomes included favorable functional outcome (mRS ≤3), functional independence (mRS ≤2), death within 90 days, National Institutes of Health Stroke Scale (NIHSS) score 24-48 hours postintervention, complications, successful reperfusion (extended Thrombolysis in Cerebral Ischemia 2B-3), and procedure duration analyzed with multivariable logistic and linear regression analyses. Results We included 264 patients (42% women). Compared with men, women were older (median age 68 vs 63 years), more often had prestroke disability (mRS ≥1: 37% vs 30%), and received intravenous thrombolytics less often (45% vs 56%). Clinical outcomes were similar between sexes (adjusted (common) OR (aOR) 0.82, 95% CI 0.51 to 1.34; favorable functional outcome 50% vs 43%, aOR 1.31, 95% CI 0.77 to 2.25; death 32% vs 29%, aOR 0.98, 95% CI 0.52 to 1.84). In addition, NIHSS score after 24-48 hours (median 7 vs 9), successful reperfusion (77% vs 73%), and complications did not differ between men and women. Conclusions Outcomes in women treated with EVT for posterior circulation LVO were similar compared with men despite less favorable baseline characteristics in women. Therefore men and women may benefit equally from EVT. [ABSTRACT FROM AUTHOR]

To fully harness mesenchymal-stromal-cells (MSCs)' benefits during Normothermic Machine Perfusion (NMP), we developed an advanced NMP platform coupled with a MSC-bioreactor and investigated its bio-molecular effects and clinical feasibility using rat and porcine models. The study involved three work packages: 1) Development (n = 5): MSC-bioreactors were subjected to 4 h-liverless perfusion; 2) Rat model (n = 10): livers were perfused for 4 h on the MSC-bioreactor-circuit or with the standard platform; 3) Porcine model (n = 6): livers were perfused using a clinical device integrated with a MSC-bioreactor or in its standard setup. MSCs showed intact stem-core properties after liverless-NMP. Liver NMP induced specific, liver-tailored, changes in MSCs' secretome. Rat livers exposed to bioreactor-based perfusion produced more bile, released less damage and pro-inflammatory biomarkers, and showed improved mithocondrial function than those subjected to standard NMP. MSC-bioreactor integration into a clinical device resulted in no machine failure and perfusion-related injury. This proof-of-concept study presents a novel MSC-based liver NMP platform that could reduce the deleterious effects of ischemia/reperfusion before transplantation. MSCs-based therapies have broad application potential in reducing ischemia/reperfusion injury, but their use for treating isolated organs before transplantation remains limited. Here, the authors present a new technology, which enables to better exploit the benefits of cell-based therapies during NMP. [ABSTRACT FROM AUTHOR]

Background Competitive leptomeningeal flow (CLF) can be observed immediately after mechanical thrombectomy (MT) reperfusion with retrograde contrast clearing of the distal leptomeningeal branches from non-contrast opacified flow through different vascular territories. We aim to evaluate the frequency of the CLF phenomenon, to determine if it has an association with the degree of leptomeningeal collateral status, and to understand the potentia impact it may have on the final expanded Treatment in Cerebral Ischemia (eTICI) score rating. Methods Retrospective analysis of a prospective MT database spanning November 2020 to December 2021. Consecutive cases of intracranial internal carotid (i-ICA) or middle cerebral artery (MCA) M1 occlusions were included. CLF was defined by the observation of retrograde clearing of distal MCA branches that were previously opacified by antegrade reperfusion. The clearance of the distal branches is presumed to occur due to CLF via non-contrast opacified posterior cerebral artery or anterior cerebral artery flow. The washout was considered CLF if it cleared abruptly with or without forward reconstitution of antegrade opacification. Results A total of 125 patients met the inclusion criteria. The median age was 64 years (IQR 52.5-75) and 64 (51%) were men. The baseline median National Institutes of Health Stroke Scale score was 17 (IQR 12-22) and the Alberta Stroke Program Early CT Score was 9 (IQR 8-10). Median last known well time to puncture was 7 hours (IQR 4-13.1) and 30.4% received tissue plasminogen activator. Final eTICI 2c-3 was achieved in 80%. CLF was present in 32 (25.6%) patients, who had comparable baseline characteristics to patients without CLF. Twelve (37.5%) patients had regional CLF and 20 (62.5%) had focal CLF. The CLF arm had better leptomeningeal single-phase CTA collaterals than the non-CLF arm (P=0.01). The inter-rater agreement for the eTICI score was moderate when CLF was present and strong in its absence (Krippendorf's alpha=0.65 and 0.81, respectively). There was minimal agreement (Kappa=0.3) for the presence versus absence of CLF between the two operators, possibly related to reader experience. Conclusion CLF was observed in 32% of patients, was associated with better collateral flow, and impacted the reported procedural eTICI rating. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusions Machine perfusion is a promising strategy for safeguarding liver transplants donated after cardiac death (DCD). In this study, we developed and validated a novel machine perfusion approach for mitigating risk factors and salvaging severe DCD livers.A novel hypothermic oxygenated perfusion (HOPE) system was developed, incorporating two pumps and an elastic water sac to emulate the functionality of the cardiac cycle. Compared to conventional systems (HOPE S1 and S2), the novel HOPE system (HOPE S3) was evaluated in rats, utilizing healthy livers perfused with methylene blue diluted using Histidine‐tryptophan‐ketoglutarate (HTK) solution or DCD livers subjected to 60 min of warm ischemia without heparin administration. Liver perfusion outcomes were assessed through macroscopic and microscopic evaluations, molecular analyses, and orthotopic liver transplantation (OLT).DCD livers subjected to HOPE systems' perfusion exhibited decreased injury and enhanced survival rates compared to static cold storage following 60 min of warm ischemia (DCD + SCS). The 4‐week post‐transplantation survival rates were 0%, 20%, and 33% in the DCD + SCS, HOPE S1, and HOPE S2 groups, respectively. HOPE S3 conferred protection against hepatocyte and non‐parenchymal cell injury, resulting in a 67% animal survival rate following 60 min of warm donor ischemia (HOPE S3). Assessments of hepatic sinusoidal microcirculation, morphological changes, and molecular alterations in preserved livers further confirmed these findings.The newly devised machine perfusion system can enhance and uniform liver perfusion and may become a promising tool for revitalizing DCD liver grafts afflicted with severe warm ischemic injuries. [ABSTRACT FROM AUTHOR]

Urinary biomarker studies in cardiothoracic and kidney-sparing surgery have demonstrated renal protection by Remote Ischaemic PreConditioning (RIPC). RIPC intervention generates cycles of ischaemia and reperfusion of the limbs before the actual ischaemia of the target organ (e.g. kidney) is initiated. This explorative trial aims to investigate whether Blood Oxygenation Level Dependent-MRI (BOLD-MRI) can be a suitable technique to image and quantify the renoprotective effect of RIPC on ischaemia/reperfusion injury (IRI) after partial nephrectomy (PN). Overall, 15 patients were enrolled in this randomized controlled trial. Randomization was 1:1, with RIPC in the intervention arm. Urinary neutrophil gelatinase-associated lipocalin (NGAL), a sensitive biomarker for renal tubular damage was measured preoperatively and for the first 5 days after surgery. Functional BOLD-MRI was successfully performed preoperatively and 48 h after PN in 11 patients. BOLD-MRI uses ∆R2* to express acute tubular damage induced by IRI. The more the ∆R2* values have decreased postoperatively, the more damage the renal tubuli have taken. The cumulative urinary concentration of NGAL in the first 5 postoperative days was significantly lower in the RIPC group (p = 0.02) as compared to the control arm, indicating that the RIPC maneuver performed was effective. The highest difference was seen 6 h after surgery with NGAL being 65% lower in the RIPC arm. IRI of the operated kidney expressed by ∆R2* in BOLD-MRI was 2.1 times less pronounced in the RIPC group as compared to the noRIPC group (∆R2* in % preop/postop RIPC: 14.73/12.57 vs. noRIPC 16.33/11.82, p = 0.36). We were able to demonstrate the potential of BOLD-MRI in measuring IRI. For the first time, it was shown that the renoprotective effects of RIPC can be visualized and measured using BOLD-MRI. Larger studies are required to validate these initial findings. [ABSTRACT FROM AUTHOR]

Currently, the barrier to successful lung transplantation is ischemia and reperfusion injury, which can lead to the development of bronchiolitis obliterans. Paclitaxel and methotrexate are drugs known to inhibit cell proliferation and have anti-inflammatory effects, and the association of these drugs with cholesterol-rich nanoparticles has been shown to be beneficial in the treatment of other transplanted organs. Thirty-three male Sprague Dawley rats were divided into 3 groups: Basal group, no intervention; Control group, received only nanoparticles; Drug group, paclitaxel and methotrexate treatment. Donors and recipients were treated with nanoparticle-paclitaxel and nanoparticle-methotrexate, respectively, 24 h before surgery. The donor lungs from the Drug group were perfused with a preservation solution supplemented with nanoparticles-paclitaxel. After 12 h, the left lung was implanted and reperfused for 1 h. Recipients had an increase in erythrocytes, neutrophils and hemoglobin and a decrease in lymphocytes, and an increase in oxygenation and lactate and a decrease in carbon dioxide. These animals showed an increase in urea and creatinine. The grafts showed perivascular edema and hemorrhage, as well as elevated values of airway resistance, tissue resistance and tissue elastance under mechanical ventilation. The tested drugs were not effective in attenuating the effects of ischemia and reperfusion injury. [ABSTRACT FROM AUTHOR]

Myocardial ischemia‐reperfusion injury (MIRI) significantly worsens the outcomes of patients with cardiovascular diseases. Dexmedetomidine (Dex) is recognized for its cardioprotective properties, but the related mechanisms, especially regarding metabolic reprogramming, have not been fully clarified. A total of 60 patients with heart valve disease are randomly assigned to Dex or control group. Blood samples are collected to analyze cardiac injury biomarkers and metabolomics. In vivo and vitro rat models of MIRI are utilized to assess the effects of Dex on cardiac function, lactate production, and mitochondrial function. It is found that postoperative CK‐MB and cTNT levels are significantly lower in the Dex group. Metabolomics reveals that Dex regulates metabolic reprogramming and reduces lactate level. In Dex‐treated rats, the myocardial infarction area is reduced, and myocardial contractility is improved. Dex inhibits glycolysis, reduces lactate, and improves mitochondrial function following MIRI. Lactylation proteomics identifies that Dex reduces the lactylation of Malate Dehydrogenase 2（MDH2), thus alleviating myocardial injury. Further studies reveal that MDH2 lactylation induces ferroptosis, leading to MIRI by impairing mitochondrial function. Mechanistic analyses reveal that Dex upregulates Nuclear Receptor Subfamily 3 Group C Member 1（NR3C1) phosphorylation, downregulates Pyruvate Dehydrogenase Kinase 4 (PDK4), and reduces lactate production and MDH2 lactylation. These findings provide new therapeutic targets and mechanisms for the treatment for MIRI. [ABSTRACT FROM AUTHOR]

Heart transplantation remains the ultimate treatment strategy for neonates and children with medically refractory end-stage heart failure and utilization of donors after circulatory death (DCD) can expand th donor pool. We have previously shown that mitochondrial transplantation preserves myocardial function and viability in neonatal swine DCD hearts to levels similar to that observed in donation after brain death (DBD). Herein, we sought to investigate the transcriptomic and proteomic pathways implicated in these phenotypic changes using ex situ perfused swine hearts. Pathway analysis showed that ATP binding, voltage-gated K channel activity involved in cardiac cell muscle contraction and ribosomal RNA biogenesis were upregulated in the mitochondrial transplantation group, while mitochondria were the predicted source. Promotion of ribosome biogenesis and downregulation of apoptosis were the overlapping mechanisms between transcriptomic and proteomic alterations. Moreover, we showed that mitochondrial transplantation modulates ischemic transcriptomic and proteomic profiles to that of non-ischemia through the mitochondria. Replication of these findings in human in vivo experiments is warranted. [ABSTRACT FROM AUTHOR]

Severity and outcome of strokes following cerebral hypoperfusion are significantly influenced by stress responses of the blood vessels. In this context, brain endothelial cells (BEC) regulate inflammation, angiogenesis and the vascular resistance to rapidly restore perfusion. Despite the relevance of these responses for infarct volume and tissue recovery, their transcriptional control in BEC is not well characterized. We revealed that oxygen and nutrient-deprived BEC activate nuclear factor of activated T-cells 5 (NFAT5)—a transcription factor that adjusts the cellular transcriptome to cope with environmental stressors. We hypothesized that NFAT5 controls the expression of genes regulating the response of BEC in the ischemic brain. The functional relevance of NFAT5 was assessed in mice, allowing the conditional EC-specific knock-out of Nfat5 (Nfat5(EC)−/−). Cerebral ischemia was induced by transient middle cerebral artery occlusion (MCAO) followed reperfusion up to 28 days. While loss of endothelial Nfat5 did not evoke any phenotypic abnormalities in mice under control conditions, infarct volumes, neurological deficits and the degree of brain atrophy were significantly pronounced following MCAO as compared to control animals (Nfat5fl/fl). In contrast, MCAO-induced edema formation, inflammatory processes and angiogenesis were not altered in Nfat5(EC)−/− mice. RNAseq analyses of cultured BEC suggested that loss of NFAT5 impairs the expression of Kcnj2 encoding a potassium channel that may affect reperfusion. In fact, lower levels of KCNJ2 were detected in arterial endothelial cells of Nfat5(EC)−/− versus Nfat5fl/fl mice. Laser speckle contrast imaging of the brain revealed an impaired perfusion recovery in Nfat5(EC)−/− versus Nfat5fl/fl mice after MCAO.Collectively, NFAT5 in arterial BEC is required for an adequate reperfusion response after brain ischemia that is presumably dependent on the maintenance of Kcnj2 expression. Consequently, impairment of the protective role of endothelial NFAT5 results in enlarged infarct sizes and more severe functional deficits of brain functions. [ABSTRACT FROM AUTHOR]

Ischaemic heart disease remains a leading cause of premature mortality and morbidity. Understanding the associated pathophysiological mechanisms of cardiac dysfunction arising from ischaemic heart disease and the identification of sites for new therapeutic interventions requires a preclinical model that reproduces the key clinical characteristics of myocardial ischaemia, reperfusion and infarction. Here, we describe and validate a refined and minimally invasive translationally relevant approach to induce ischaemia, reperfusion and infarction in the sheep. The novelty and refinement in the procedure stems from utilization of implantable cardiac defibrillators prior to coronary engagement, balloon angioplasty to induce infarction, and intra‐operative anti‐arrhythmic drug protocols to reduce adverse arrhythmic events. The protocol is readily adoptable by researchers with access to standard fluoroscopic instrumentation, and it requires minimally invasive surgery. These refinements lead to a substantial reduction of intra‐operative mortality to 6.7% from previously published values ranging between 13% and 43%. The model produces key characteristics associated with the fourth universal definition of myocardial infarction, including ECG changes, elevated cardiac biomarkers and cardiac wall motility defects. In conclusion, the model closely replicates the clinical paradigm of myocardial ischaemia, reperfusion and infarction in a translationally relevant large animal setting, and the applied refinements reduce the incidence of intra‐operative mortality typically associated with preclinical myocardial infarction models. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) induced by renal ischemia–reperfusion injury (IRI) has a high morbidity and mortality, representing a worldwide problem. The kidney is an essential organ of metabolism that has high blood perfusion and is the second most mitochondria‐rich organ after the heart because of the high ATP demands of its essential functions of nutrient reabsorption, acid–base and electrolyte balance, and hemodynamics. Thus, these energy‐intensive cells are particularly vulnerable to mitochondrial dysfunction. As the bulk of glomerular ultrafiltrate reabsorption by proximal tubules occurs via active transport, the mitochondria of proximal tubules must be equipped for detecting and responding to fluctuations in energy availability to guarantee efficient basal metabolism. Any insults to mitochondrial quality control mechanisms may lead to biological disruption, blocking the clearance of damaged mitochondria and resulting in morphological change and tissue dysfunction. Extensive research has shown that mitochondria have pivotal roles in acute kidney disease, so in this article, we discuss the role of mitochondria, their dynamics and mitophagy in renal ischemia–reperfusion injury. [ABSTRACT FROM AUTHOR]

Ischemic heart disease (IHD) remains one of the most prominent causes of mortality and morbidity globally, and the risk of ischemia–reperfusion injury is becoming more severe and constant. This underscores the need to develop new methods to protect the heart from damage. DJ‐1 is a multifunctional intracellular protein encoded by the PARK7 gene that plays roles in processes including the control of autophagy, the preservation of mitochondrial integrity, the prevention of apoptosis, and the elimination of oxidative stress. DJ‐1 has recently been the focus of growing interest as a target molecule relevant to treating myocardial ischemia–reperfusion injury due to its protective properties and its role in cellular response mechanisms. Consistently, DJ‐1‐related interventions, such as its exogenous administration or the use of pharmacological agents, have been demonstrated to help protect the myocardium from ischemia–reperfusion injury and associated adverse outcomes. This review provides an overview of DJ‐1 and its therapeutic relevance in the myocardium in the setting of ischemia and reperfusion. [ABSTRACT FROM AUTHOR]

• Exercise preconditioning protects rats from I/R injury by boosting energy metabolism. • Exercise reduces harmful metabolites post-I/R, cutting oxidative stress and apoptosis. • Results show exercise eases I/R injury by regulating metabolism. Cerebral ischemia and subsequent reperfusion damage are prevalent in clinical practice, linked to numerous neurodegenerative diseases. Cerebral ischemia deprives brain tissue of essential oxygen and nutrients, disrupting energy metabolism and causing cellular dysfunction. Although reperfusion theoretically aids recovery, it instead initiates complex injury responses such as oxidative stress, apoptosis, and inflammation, worsening brain damage. Recent research suggests that enhancing neuronal energy status by modulating energy metabolism pathways can effectively counter these effects. For instance, boosting mitochondrial function, improving energy provision, and decreasing harmful metabolites can mitigate oxidative stress and cellular injury. This study investigated the protective effects of exercise preconditioning against ischemia–reperfusion injury in rats. It was observed that exercise enhances energy levels and mitochondrial respiration by upregulating the expression of COX4 and NAMPT proteins and activating AMPK and mitochondrial complex V. This process facilitates metabolic reprogramming characterized by the promotion of oxidative phosphorylation (OXPHOS) and the pentose phosphate pathway (PPP), alongside a reduction in glycolysis. Such reprogramming reduces harmful metabolites, mitigating apoptosis and oxidative stress, and is a key factor in alleviating acute ischemic hypoxia-induced brain damage. These findings introduce a novel therapeutic approach for ischemic brain reperfusion injury, underscoring the crucial role of ATP production and metabolic regulation in neuroprotection. [ABSTRACT FROM AUTHOR]

Background: Rupture of unstable coronary atherosclerotic plaque leads to acute ST-segment elevation myocardial infarction (STEMI). Dual anti-platelet therapy is one of the main treatments, and the combination of Aspirin and Clopidogrel is recognized as the standard oral regimen in most cases. Ticagrelor is a new generation of P2Y12 receptor inhibitors. We aimed to compare the effect of Ticagrelor and Clopidogrel in the treatment of patients post-STEMI. Methods: This study investigated Pub Med, Scopus, Google Scholar Web of Science, and Embase Cochrane Library clinical trials.gov databases. Heterogeneity between studies was assessed using the I2 index and the Q statistic. The random effects model was used to combine studies and the Funnel plot and Egger's test were used to assess the publication bias. Results: Eleven studies were included in this meta-analysis. 5274 patients in the Ticagrelor and 5,295 patients in the Clopidogrel groups were examined. The mean age of the patients was 58.84 years (2.70) and 59.92 years (3.19) in the Ticagrelor and Clopidogrel groups, respectively. Based on the results of the meta-analysis, compared to Clopidogrel, Ticagrelor had decreased the outcomes of mortality, recurrent myocardial infarction, stroke, and Major Adverse Cardiovascular Events (MACE). However, the post-myocardial infarction bleeding according to Bleeding Academic Research Consortium (BARC) criteria and reperfusion state regarding thrombolysis in myocardial infarction (TIMI) Flow Grading system showed no differences in both groups. However, these effects were not statistically significant. Conclusions: Ticagrelor decreased the chance of mortality, re-infarction, stroke, and MACE in post-STEMI patients compared to clopidogrel. But there was no difference in the chance of major bleedings (BARC ≥ 3) and improvement in TIMI grade flow between these two drugs. However, none of these findings were statistically significant, and more studies are needed to reach definitive results. [ABSTRACT FROM AUTHOR]

Purpose: The aims of this study are to explore the apparent diffusion coefficient (ADC)-dependent thresholds for time to reperfusion in reversible lesions following mechanical thrombectomy for acute ischemic stroke, and to investigate the associated risks of hemorrhagic transformation. Methods: We conducted a retrospective case-control study, enrolling patients with large-vessel occlusion who underwent mechanical thrombectomy in Otaru General Hospital from 2016 to 2021. Reversible lesions were identified using volumetric ADC data, and the mean time from image to reperfusion (TIR) in each ADC range was compared between groups with and without reversible lesions, as well as those with and without parenchymal hematoma. The Wilcoxon rank sum test and chi-square test were used for comparison between two groups, and receiver operating characteristic curves were created to determine optimal thresholds. Results: Seventy-five patients were included and 581 volumetric data were obtained. The mean TIR in the group with reversible lesions was shorter than in that without, and time thresholds were 131, 123 and 112 min for ADC values > 540 × 10−6, 500–540 × 10−6 and 440–500 × 10−6 mm2/s, respectively. Furthermore, in patients with parenchymal hematoma, the mean TIR was significantly longer, and the average ADC value was significantly lower than those without hematoma. Conclusion: The time thresholds for the irreversible ischemic core may vary depending on the ADC value, and they may be shorter when the ADC value is lower. Moreover, both the low ADC value and the late reperfusion might be associated with an increased risk of parenchymal hematoma. [ABSTRACT FROM AUTHOR]

Purpose: For nearly half of patients who undergo Endovascular Thrombectomy following ischemic stroke, successful recanalisation does not guarantee a good outcome. Understanding the underlying tissue changes in the infarct tissue with the help of biomarkers specific to ischemic stroke could offer valuable insights for better treatment and patient management decisions. Using quantitative susceptibility mapping (QSM) MRI to measure cerebral iron concentration, this study aims to track the progression of iron within the infarct lesion after successful reperfusion. Methods: In a prospective study of 87 ischemic stroke patients, successfully reperfused patients underwent MRI scans at 24-to-72 h and 3 months after reperfusion. QSM maps were generated from gradient-echo MRI images. QSM values, measured in parts per billion (ppb), were extracted from ROIs defining the infarct and mirror homolog in the contralateral hemisphere and were compared cross-sectionally and longitudinally. Results: QSM values in the infarct ROIs matched those of the contralateral ROIs at 24-to-72 h, expressed as median (interquartile range) ppb [0.71(-7.67-10.09) vs. 2.20(-10.50-14.05) ppb, p = 0.55], but were higher at 3 months [10.68(-2.30-21.10) vs. -1.27(-12.98-9.82) ppb, p < 0.001]. The infarct QSM values at 3 months were significantly higher than those at 24-to-72 h [10.41(-2.50-18.27) ppb vs. 1.68(-10.36-12.25) ppb, p < 0.001]. Infarct QSM at 24-to-72 h and patient outcome measured at three months did not demonstrate a significant association. Conclusion: Following successful endovascular reperfusion, iron concentration in infarct tissue, as measured by QSM increases over time compared to that in healthy tissue. However, its significance warrants further investigation. [ABSTRACT FROM AUTHOR]

Liver ischemia‐reperfusion (I/R) injury is a common cause of organ failure, developed by a sudden block in the blood and oxygen supply and subsequent restoration. I/R damage is responsible for acute and chronic rejection after organ transplantation, accounting for 10% of early graft failure. The study investigated the therapeutic properties of fangchinoline in liver injury‐induced rats. The rats were divided into three groups: Sham, I/R without pretreatment, and I/R + 10 mg/kg fangchinoline pretreatment. Blood and liver samples were collected for assays, and an in silico docking analysis was conducted to determine fangchinoline's inhibitory effect. The pretreatment with 10 mg/kg of fangchinoline effectively reduced hepatic marker enzymes such as AST, LDH, and ALT in the serum of rats with liver I/R damage. Fangchinoline treatment significantly reduced interleukin‐8 (IL‐8), IL‐6, and tumor necrosis factor‐α (TNF‐α) in I/R‐induced rats, boosting antioxidants and decreasing MDA. Histopathological studies showed liver injury protection, and fangchinoline inhibited TNF‐α and IL‐6 with improved binding affinity. Fangchinoline has hepatoprotective properties by reducing inflammation in rats with liver I/R damage, as demonstrated in the current study. Hence, it can be an effective salutary agent in preventing liver damage caused by I/R. [ABSTRACT FROM AUTHOR]

Background: Cardiac arrest is associated with high mortality rates and severe neurological impairments. One of the underlying mechanisms is global ischemia‐reperfusion injury of the body, particularly the brain. Strategies to mitigate this may thus improve favorable neurological outcomes. The use of extracorporeal cardiopulmonary membrane oxygenation (ECMO) during CA has been shown to improve survival, but available systems are vastly unable to deliver goal‐oriented resuscitation to control patient's individual physical and chemical needs during reperfusion. Recently, controlled automated reperfusion of the whoLe body (CARL), a pulsatile ECMO with arterial blood‐gas analysis, has been introduced to deliver goal‐directed reperfusion therapy during the post‐arrest phase. Methods: This review focuses on the device profile and use of CARL. Specifically, we reviewed the published literature to summarize data regarding its technical features and potential benefits in ECPR. Results: Peri‐arrest, mitigating severe IRI with ECMO, might be the next step toward augmenting survival rates and neurological recovery. To this end, CARL is a promising extracorporeal oxygenation device that improves the early reperfusion phase after resuscitation. [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]

Objective: This study aimed to investigate the mechanism of emulsified isoflurane in reducing myocardial ischemia-reperfusion injury (MIRI). Materials and methods: Forty-eight healthy male Sprague-Dawley rats were randomly divided into four groups (n = 12). In the sham group (group S) and ischemia-reperfusion group (group I/R), saline (4 ml/kg/h) was administered intravenously for 30 min. In intralipid group (group L), intralipid (4 ml/kg/h) was administered intravenously. In the emulsified isoflurane group (group EI), emulsified isoflurane (4 ml/kg/h) was administered intravenously. The infusion was then discontinued for 15 min during the washout period. Apart from group S, ischemia was produced by occlusion of the left anterior descending artery (LADA) for 30 min. After 30 min of occlusion, all groups received reperfusion for two hours. Results: Creatine kinase MB (CK-MB), cardiac troponin I (cTnI), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA). Myocardial infarct size was measured using triphenyl tetrazolium chloride staining. According to the result, pretreatment with emulsified isoflurane attenuated CK-MB and cTnI concentrations (p < 0.05). And serum TNF-α and IL-6 levels and infarct size in the emulsified isoflurane group obviously decreased. An obvious decrease in the expression of the toll-like receptor-4 (TLR-4) mRNA in group EI was observed compared with group I/R. Discussion and conclusion: Emulsified isoflurane precondition had a potent cardioprotective effect against myocardial ischemia-reperfusion injury. The mechanisms involved may be related to the decrease in the expression of TLR-4 and the reduced inflammatory response. [ABSTRACT FROM AUTHOR]

Simple Summary: Connexins are membrane proteins forming gap junctions essential for intercellular communication. Connexin 43 (Cx43), encoded by GJA1, is the most abundant connexin, especially in the heart. Cx43-based gap junctions enable the direct intercellular transport of ions, critical for cardiac rhythm by synchronizing electrical impulses between heart cells. The isoform GJA1-20k, derived from an internal translation start site of the same GJA1 mRNA, has important roles beyond cell-to-cell communication. GJA1-20k aids in Cx43 trafficking to specific membrane subdomains and is crucial for cytoskeletal organization and mitochondrial stability. GJA1-20k also influences mitochondrial distribution and promotes mitochondrial fission, helping cells manage oxidative stress. Reduced GJA1-20k levels are associated with disrupted Cx43 trafficking and mitochondrial dysfunction, contributing to cardiovascular diseases such as arrhythmias and heart failure. GJA1-20k's potent roles in regulating the cytoskeleton, Cx43 transport, and mitochondrial homeostasis makes it a promising therapeutic target. Connexin 43 (Cx43) is an essential regulator in cardiovascular physiology, responsible for intercellular communication within the heart. The role of Cx43 in maintaining beat-to-beat cardiac excitation and cardiac function underscores its significance. Alterations in Cx43 expression and localization have been implicated in pathologies from sudden cardiac death to heart failure. Essential to Cx43 function is its intrinsic ability to form diverse isoforms through internal translation of GJA1 mRNA. Evidence has accumulated that GJA1-20k, the most abundant of these isoforms, is necessary for Cx43 trafficking and localization. GJA1-20k has been recognized to have a wide range of additional functions beyond directing Cx43-based intercellular communication, including cytoskeletal modulation, maintaining mitochondrial homeostasis, protecting against oxidative stress, and mediating mitochondrial preconditioning. The involvement of GJA1-20k in these processes confers it great therapeutic potential, especially in treating cardiovascular diseases such as myocardial infarction, ischemia/reperfusion injuries, and arrhythmias. Administration of GJA1-20k mitigates the underlying cellular pathophysiological disturbances that develop as a result of these diseases. Numerous studies have documented the therapeutic efficacy of GJA1-20k gene therapy in animal models of cardiovascular disease. The translational impact of these studies opens up new treatment avenues through the use of gene therapy targeting novel mechanisms of action. [ABSTRACT FROM AUTHOR]

Background: Torsion of the spermatic cord is a hazardous and common urologic issue. The current work evaluates the possible protective effect of pregabalin (PGB) and xanthenone (XAN) in testicular ischemia/reperfusion injury induced by testicular torsion/detorsion in rats. Materials and methods: Seven groups of adult male Wistar albino rats were allocated randomly into seven groups, namely, sham control, torsion/detorsion (T/D), PGB 50 mg/kg, PGB 100 mg/kg, XAN 1 mg/kg, XAN 2 mg/kg, and PGB 50 mg/kg plus XAN 1 mg/kg groups. Serum cholesterol and testosterone levels were determined. Also, the levels of malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), superoxide dismutase (SOD), tumor necrosis factor‐α (TNF‐α), nuclear factor kappa B (NF‐қB), angiotensin (Ang) II, Ang‐(1–7), and angiotensin‐converting enzyme2 (ACE2) were assessed in testicular tissue. Immunohistochemical analysis of heme oxygenase‐1 (HO‐1) and caspase‐3 was performed. Finally, the histopathological examination of the testicular tissues was performed. Results: The PGB 50 mg/kg, PGB 100 mg/kg, XAN 1 mg/kg, XAN 2 mg/kg, and PGB 50 mg/kg plus XAN 1 mg/kg groups showed a significant decrease in serum cholesterol, MDA, NO, TNF‐α, NF‐қB, and Ang‐II levels coupled with a significant increase in both testosterone and ACE2 expression. Furthermore, all test groups showed a significant improvement in the histopathological picture with a reduction in caspase‐3 and an increase in HO‐1 immunoexpression in testicular tissue. Conclusion: PGB and XAN may have promising effects on preventing testicular T/D injury through antioxidant, anti‐inflammatory, and antiapoptotic actions. [ABSTRACT FROM AUTHOR]

Background: Renal ischemia reperfusion injury (IRI) is a post‐ischemic event, which can lead to subsequent acute kidney injury (AKI), transplant failure, renal dysfunction and fibrosis via heightened oxidative stress and production of inflammatory cytokines and chemokines. Objective: This study aims to assess the effect of Modafinil, a wake‐promoting agent with previously proven anti‐inflammatory and anti‐oxidative properties, on ameliorating renal IRI. Methods: A total of 30 male Wistar rats were divided into five groups: Sham‐operated group, ischemia reperfusion (I/R) control group and Modafinil pre‐treated groups (at different doses of 50, 100 and 150 mg/kg). IRI was induced by means of bilaterally clamping the renal arteries for 45 min, followed by 24 h of reperfusion. Results: Tissue pathological assessments demonstrated a reduction of glomerular, vascular and interstitial injury at doses of 50 and 100 mg/kg of Modafinil. The biochemical studies showed a significant decrease in tissue pro‐inflammatory factors, including tumor necrosis factor alpha (TNF‐α), Interleukin‐18 (IL‐18) and lactate dehydrogenase (LDH). Moreover, an elevation was observed in levels of super oxide dismutase (SOD) and catalase, indicating the reduction of oxidative stress. Furthermore, the levels of creatinine (Cr), urea and neutrophil gelatinase‐associated lipocalin (NGAL) were declined, indicating the improvement in renal function at effective doses of Modafinil (50 and 100 mg/kg) compared to the I/R control group without Modafinil pre‐treatment. Conclusion: Our findings suggest that Modafinil holds promise as an effective therapeutic agent to address the clinical challenges associated with kidney IRI reducing the need for hospitalization and potentially alleviating related morbidities. [ABSTRACT FROM AUTHOR]

Objectives: Distant liver injury is a complication of renal ischemia-reperfusion (I/R) injury, which imposes mortality and economic burden. This study aimed to elucidate the cross-talk of endoplasmic reticulum (ER) stress and mitochondrial perturbations in renal I/R-induced liver injury, and the potential hepatoprotective effect of azilsartan (AZL). Methods: Male albino Wister rats were pre-treated with AZL (3 mg/kg/day, PO) for 7 days then a bilateral renal I/R or sham procedure was performed. Activities of liver enzymes were assessed in plasma. The structure and ultra-structure of hepatocytes were assessed by light and electron microscopy. Markers of ER stress, mitochondrial biogenesis and apoptosis were analyzed in livers of rats. Results: Renal ischemic rats showed higher plasma levels of liver enzymes than sham-operated rats, coupled with histological and ultra-structural alterations in hepatocytes. Mechanistically, there was up-regulation of ER stress markers and suppression of mitochondrial biogenesis-related proteins and enhanced apoptosis in livers of renal ischemic rats. These abnormalities were almost abrogated by AZL pretreatment. Discussion: Our findings uncovered the involvement of mitochondrial perturbations, ER stress and apoptosis in liver injury following renal I/R, and suggested AZL as a preconditioning strategy to ameliorate remote liver injury in patients susceptible to renal I/R after adequate clinical testing. [ABSTRACT FROM AUTHOR]