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International Journal of Molecular... Nov 2023Ischemia is the main cause of cell death in retinal diseases such as vascular occlusions, diabetic retinopathy, glaucoma, or retinopathy of prematurity. Although...
Ischemia is the main cause of cell death in retinal diseases such as vascular occlusions, diabetic retinopathy, glaucoma, or retinopathy of prematurity. Although excitotoxicity is considered the primary mechanism of cell death during an ischemic event, antagonists of glutamatergic receptors have been unsuccessful in clinical trials with patients suffering ischemia or stroke. Our main purpose was to analyze if the transient receptor potential channel 7 (TRPM7) could contribute to retinal dysfunction in retinal pathologies associated with ischemia. By using an experimental model of acute retinal ischemia, we analyzed the changes in retinal function by electroretinography and the changes in retinal morphology by optical coherence tomography (OCT) and OCT-angiography (OCTA). Immunohistochemistry was performed to assess the pattern of TRPM7 and its expression level in the retina. Our results show that ischemia elicited a decrease in retinal responsiveness to light stimuli along with reactive gliosis and a significant increase in the expression of TRPM7 in Müller cells. TRPM7 could emerge as a new drug target to be explored in retinal pathologies associated with ischemia.
Topics: Animals; Humans; Infant, Newborn; Mice; Ischemia; Protein Serine-Threonine Kinases; Reperfusion; Retina; Retinal Diseases; Retinal Vessels; TRPM Cation Channels
PubMed: 38003256
DOI: 10.3390/ijms242216068 -
Journal of the American College of... Jun 2024Despite impressive improvements in the care of patients with ST-segment elevation myocardial infarction, mortality remains high. Reperfusion is necessary for myocardial... (Review)
Review
Despite impressive improvements in the care of patients with ST-segment elevation myocardial infarction, mortality remains high. Reperfusion is necessary for myocardial salvage, but the abrupt return of flow sets off a cascade of injurious processes that can lead to further necrosis. This has been termed myocardial ischemia-reperfusion injury and is the subject of this review. The pathologic and molecular bases for myocardial ischemia-reperfusion injury are increasingly understood and include injury from reactive oxygen species, inflammation, calcium overload, endothelial dysfunction, and impaired microvascular flow. A variety of pharmacologic strategies have been developed that have worked well in preclinical models and some have shown promise in the clinical setting. In addition, there are newer mechanical approaches including mechanical unloading of the heart prior to reperfusion that are in current clinical trials.
Topics: Humans; Myocardial Reperfusion Injury; Myocardial Infarction; Myocardial Reperfusion; ST Elevation Myocardial Infarction
PubMed: 38811097
DOI: 10.1016/j.jacc.2024.02.056 -
Frontiers in Neurology 2023The impact of COVID-19 on clinical outcomes in acute ischemic stroke patients receiving reperfusion therapy remains unclear. We therefore aimed to synthesize the... (Review)
Review
BACKGROUND
The impact of COVID-19 on clinical outcomes in acute ischemic stroke patients receiving reperfusion therapy remains unclear. We therefore aimed to synthesize the available evidence to investigate the safety and short-term efficacy of reperfusion therapy in this patient population.
METHODS
We searched the electronic databases MEDLINE, Embase and Cochrane Library Reviews for randomized controlled trials and observational studies that investigated the use of intravenous thrombolysis, endovascular therapy, or a combination of both in acute ischemic stroke patients with laboratory-confirmed COVID-19, compared to controls. Our primary safety outcomes included any intracerebral hemorrhage (ICH), symptomatic ICH and all-cause in-hospital mortality. Short-term favorable functional outcomes were assessed at discharge and at 3 months. We calculated pooled risk ratios (RR) and 95% confidence intervals (CI) using DerSimonian and Laird random-effects model. Heterogeneity was evaluated using Cochran's Q test and statistics.
RESULTS
We included 11 studies with a total of 477 COVID-19 positive and 8,092 COVID-19 negative ischemic stroke patients who underwent reperfusion therapy. COVID-19 positive patients exhibited a significantly higher risk of experiencing any ICH (RR 1.54, 95% CI 1.16-2.05, < 0.001), while the nominally increased risk of symptomatic ICH in these patients did not reach statistical significance (RR 2.04, 95% CI 0.97-4.31; = 0.06). COVID-19 positive stroke patients also had a significantly higher in-hospital mortality compared to COVID-19 negative stroke patients (RR 2.78, 95% CI 2.15-3.59, < 0.001). Moreover, COVID-19 positive stroke patients were less likely to achieve a favorable functional outcome at discharge (RR 0.66, 95% CI 0.51-0.86, < 0.001) compared to COVID-19 negative patients, but this difference was not observed at 3-month follow-up (RR 0.64, 95% CI 0.14-2.91, = 0.56).
CONCLUSION
COVID-19 appears to have an adverse impact on acute ischemic stroke patients who undergo reperfusion therapy, leading to an elevated risk of any ICH, higher mortality and lower likelihood of favorable functional outcome.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO, identifier CRD42022309785.
PubMed: 37681003
DOI: 10.3389/fneur.2023.1239953 -
Neurochemistry International Dec 2023DJ-1 has been confirmed to have neuroprotective effects. Ferroptosis is an iron-dependent programmed cell death mode associated with ischemic stroke. The ATF4/HSPA5...
DJ-1 has been confirmed to have neuroprotective effects. Ferroptosis is an iron-dependent programmed cell death mode associated with ischemic stroke. The ATF4/HSPA5 pathway has been shown to play an important role in the regulation of ferroptosis. To explore the role and possible mechanism of DJ-1 in regulating ferroptosis in cerebral ischemia-reperfusion injury. In this study, Middle cerebral artery occlusion/reperfusion (MCAO/R) was used to simulate cerebral ischemia-reperfusion injury in vivo. Detected ferroptosis-related indicators and observed mitochondrial morphology in brain tissue using transmission electron microscopy. ATF4 was subsequently interfered to observe the effect of DJ-1 on ferroptosis. The results suggest that after interfering with DJ-1, the iron content and malondialdehyde (MDA) content of ferroptosis-related indicators increased, the GSH content decreased, and the mitochondrial structure was severely damaged. We then found that DJ-1 attenuated ferroptosis following ATF4 reduction. In this study, we found that the neuroprotective effect of DJ-1 is related to the inhibition of ferroptosis, and its molecular mechanism is closely related to the ATF4/HSPA5 pathway, which may play a key role in inhibiting brain ischemia-reperfusion (I/R) ferroptosis.
Topics: Humans; Ferroptosis; Brain Ischemia; Infarction, Middle Cerebral Artery; Reperfusion Injury; Neuroprotective Agents; Reperfusion; Iron; Activating Transcription Factor 4
PubMed: 37820776
DOI: 10.1016/j.neuint.2023.105628 -
Free Radical Biology & Medicine Aug 2023Myocardial ischemia-reperfusion (IR) injury may result in cardiomyocyte dysfunction. Mitochondria play a critical role in cardiomyocyte recovery after IR injury. The...
Myocardial ischemia-reperfusion (IR) injury may result in cardiomyocyte dysfunction. Mitochondria play a critical role in cardiomyocyte recovery after IR injury. The mitochondrial uncoupling protein 3 (UCP3) has been proposed to reduce mitochondrial reactive oxygen species (ROS) production and to facilitate fatty acid oxidation. As both mechanisms might be protective following IR injury, we investigated functional, mitochondrial structural, and metabolic cardiac remodeling in wild-type mice and in mice lacking UCP3 (UCP3-KO) after IR. Results showed that infarct size in isolated perfused hearts subjected to IR ex vivo was larger in adult and old UCP3-KO mice than in equivalent wild-type mice, and was accompanied by higher levels of creatine kinase in the effluent and by more pronounced mitochondrial structural changes. The greater myocardial damage in UCP3-KO hearts was confirmed in vivo after coronary artery occlusion followed by reperfusion. S1QEL, a suppressor of superoxide generation from site I in complex I, limited infarct size in UCP3-KO hearts, pointing to exacerbated superoxide production as a possible cause of the damage. Metabolomics analysis of isolated perfused hearts confirmed the reported accumulation of succinate, xanthine and hypoxanthine during ischemia, and a shift to anaerobic glucose utilization, which all recovered upon reoxygenation. The metabolic response to ischemia and IR was similar in UCP3-KO and wild-type hearts, being lipid and energy metabolism the most affected pathways. Fatty acid oxidation and complex I (but not complex II) activity were equally impaired after IR. Overall, our results indicate that UCP3 deficiency promotes enhanced superoxide generation and mitochondrial structural changes that increase the vulnerability of the myocardium to IR injury.
Topics: Mice; Animals; Superoxides; Myocardial Ischemia; Myocytes, Cardiac; Mitochondria; Oxidative Stress; Myocardial Reperfusion Injury; Coronary Artery Disease; Energy Metabolism; Ischemia; Reperfusion; Fatty Acids; Infarction
PubMed: 37295539
DOI: 10.1016/j.freeradbiomed.2023.05.014 -
Arquivos Brasileiros de Cardiologia 2024Early reperfusion therapy is acknowledged as the most effective approach for reducing case fatality rates in patients with ST-segment elevation myocardial infarction...
BACKGROUND
Early reperfusion therapy is acknowledged as the most effective approach for reducing case fatality rates in patients with ST-segment elevation myocardial infarction (STEMI).
OBJECTIVE
Estimate the clinical and economic consequences of delaying reperfusion in patients with STEMI.
METHODS
This retrospective cohort study evaluated mortality rates and the total expenses incurred by delaying reperfusion therapy among 2622 individuals with STEMI. Costs of in-hospital care and lost productivity due to death or disability were estimated from the perspective of the Brazilian Unified Health System indexed in international dollars (Int$) adjusted by purchase power parity. A p < 0.05 was considered statistically significant.
RESULTS
Each additional hour of delay in reperfusion therapy was associated with a 6.2% increase (95% CI: 0.3% to 11.8%, p = 0.032) in the risk of in-hospital mortality. The overall expenses were 45% higher among individuals who received treatment after 9 hours compared to those who were treated within the first 3 hours, primarily driven by in-hospital costs (p = 0.005). A multivariate linear regression model indicated that for every 3-hour delay in thrombolysis, there was an increase in in-hospital costs of Int$497 ± 286 (p = 0.003).
CONCLUSIONS
The findings of our study offer further evidence that emphasizes the crucial role of prompt reperfusion therapy in saving lives and preserving public health resources. These results underscore the urgent need for implementing a network to manage STEMI cases.
Topics: Humans; Female; Male; Retrospective Studies; ST Elevation Myocardial Infarction; Middle Aged; Time Factors; Brazil; Hospital Mortality; Aged; Time-to-Treatment; Myocardial Reperfusion; Treatment Outcome; Hospital Costs; Thrombolytic Therapy
PubMed: 38747748
DOI: 10.36660/abc.20230650 -
IScience Sep 2023A major side effect of reperfusion therapy following myocardial infarction is myocardial ischemia-reperfusion injury (MIRI). Electroacupuncture preconditioning (EA-pre)...
A major side effect of reperfusion therapy following myocardial infarction is myocardial ischemia-reperfusion injury (MIRI). Electroacupuncture preconditioning (EA-pre) has a long history in the treatment of cardiovascular diseases. Here, we demonstrate how EA-pre attenuates MIRI by affecting the phagocytosis of neuronal dendritic spines of microglia of the fastigial nucleus (FN). We observed that EA-pre increased activity in FN and then improved myocardial injury by inhibiting abnormal activities of glutaminergic neurons of the FN (FN) during MIRI. Interestingly, we observed changes in the quantity and shape of FN microglia in mice treated with EA-pre and a decrease in the phagocytosis of FN neuronal dendritic spines by microglia. Furthermore, the effects of improving MIRI were reversed when EA-pre mice were chemically activated by intra-FN lipopolysaccharide injection. Overall, our results provide new insight indicating that EA-pre regulates microglial engulfment capacity, thus promoting the improvement of cardiac sympathetic nervous disorder during MIRI.
PubMed: 37670780
DOI: 10.1016/j.isci.2023.107645 -
European Heart Journal. Acute... Oct 2023High-risk pulmonary embolism (PE) is associated with significant morbidity and mortality. Systemic thrombolysis remains the most evidenced-based treatment for...
High-risk pulmonary embolism (PE) is associated with significant morbidity and mortality. Systemic thrombolysis remains the most evidenced-based treatment for haemodynamically unstable PE, but in daily clinical practice, it remains largely underused. In addition, unlike acute myocardial infarction or stroke, a clear time window for reperfusion therapy, including fibrinolysis, for high-risk PE has not been defined either for fibrinolysis or for the more recently incorporated options of catheter-based thrombolysis or thrombectomy. The aim of the present article is to review the current evidence supporting the potential benefit of earlier administration of reperfusion in haemodynamically unstable PE patients and suggest some potential strategies to further explore this issue.
Topics: Humans; Thrombolytic Therapy; Thrombectomy; Pulmonary Embolism; Reperfusion; Treatment Outcome; Fibrinolytic Agents; Acute Disease
PubMed: 37421358
DOI: 10.1093/ehjacc/zuad080 -
Molecular and Cellular Endocrinology Jul 2023Diabetic patients are prone to acute myocardial infarction. Although reperfusion therapy can preserve the viability of the myocardium, it also causes fatal...
Diabetic patients are prone to acute myocardial infarction. Although reperfusion therapy can preserve the viability of the myocardium, it also causes fatal ischemia‒reperfusion injury. Diabetes can exacerbate myocardial ischemia‒reperfusion injury, but the mechanism is unclear. We aimed to characterize the effects of liraglutide on the prevention of ischemia‒reperfusion injury and inadequate autophagy. Liraglutide reduced the myocardial infarction area and improved cardiac function in diabetic mice. We further demonstrated that liraglutide mediated these protective effects by activating AMPK/mTOR-mediated autophagy. Liraglutide markedly increased p-AMPK levels and the LC3 II/LC3 I ratio and reduced p-mTOR levels and p62 expression. Pharmacological inhibition of mTOR increased cell viability and autophagy levels in high glucose and H/R-treated H9C2 cells. Overall, our study reveals that liraglutide acts upstream of the AMPK/mTOR pathway to effectively counteract high glucose- and H/R-induced cell dysfunction by activating AMPK/mTOR-dependent autophagy, providing a basis for the clinical prevention and treatment of ischemia‒reperfusion in diabetes.
Topics: Mice; Animals; Liraglutide; Signal Transduction; Diabetes Mellitus, Experimental; AMP-Activated Protein Kinases; Myocardial Reperfusion Injury; TOR Serine-Threonine Kinases; Myocardial Infarction; Glucose; Autophagy
PubMed: 37172886
DOI: 10.1016/j.mce.2023.111954 -
Journal of Cerebral Blood Flow and... Jun 2024Endovascular reperfusion therapy is the primary strategy for acute ischemic stroke. No-reflow is a common phenomenon, which is defined as the failure of microcirculatory... (Review)
Review
Endovascular reperfusion therapy is the primary strategy for acute ischemic stroke. No-reflow is a common phenomenon, which is defined as the failure of microcirculatory reperfusion despite clot removal by thrombolysis or mechanical embolization. It has been reported that up to 25% of ischemic strokes suffer from no-reflow, which strongly contributes to an increased risk of poor clinical outcomes. No-reflow is associated with functional and structural alterations of cerebrovascular microcirculation, and the injury to the microcirculation seriously hinders the neural functional recovery following macrovascular reperfusion. Accumulated evidence indicates that pathology of no-reflow is linked to adhesion, aggregation, and rolling of blood components along the endothelium, capillary stagnation with neutrophils, astrocytes end-feet, and endothelial cell edema, pericyte contraction, and vasoconstriction. Prevention or treatment strategies aim to alleviate or reverse these pathological changes, including targeted therapies such as cilostazol, adhesion molecule blocking antibodies, peroxisome proliferator-activated receptors (PPARs) activator, adenosine, pericyte regulators, as well as adjunctive therapies, such as extracorporeal counterpulsation, ischemic preconditioning, and alternative or complementary therapies. Herein, we provide an overview of pathomechanisms, predictive factors, diagnosis, and intervention strategies for no-reflow, and attempt to convey a new perspective on the clinical management of no-reflow post-ischemic stroke.
Topics: Humans; Ischemic Stroke; No-Reflow Phenomenon; Animals; Endovascular Procedures; Microcirculation; Cerebrovascular Circulation
PubMed: 38420850
DOI: 10.1177/0271678X241237159