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Journal of Clinical Medicine Aug 2023Cardiogenic shock is a critical condition of low cardiac output resulting in insufficient systemic perfusion and end-organ dysfunction. Though significant advances have... (Review)
Review
Cardiogenic shock is a critical condition of low cardiac output resulting in insufficient systemic perfusion and end-organ dysfunction. Though significant advances have been achieved in reperfusion therapy and mechanical circulatory support, cardiogenic shock continues to be a life-threatening condition associated with a high rate of complications and excessively high patient mortality, reported to be between 35% and 50%. Extracorporeal membrane oxygenation can provide full cardiopulmonary support, has been increasingly used in the last two decades, and can be used to restore systemic end-organ hypoperfusion. However, a paucity of randomized controlled trials in combination with high complication and mortality rates suggest the need for more research to better define its efficacy, safety, and optimal patient selection. In this review, we provide an updated review on VA-ECMO, with an emphasis on its application in cardiogenic shock, including indications and contraindications, expected hemodynamic and echocardiographic findings, recommendations for weaning, complications, and outcomes. Furthermore, specific emphasis will be devoted to the two published randomized controlled trials recently presented in this setting.
PubMed: 37685643
DOI: 10.3390/jcm12175576 -
Journal of Clinical Medicine Dec 2023While early coronary reperfusion via primary percutaneous coronary intervention (pPCI) is established as the most efficacious therapy for minimizing infarct size (IS) in... (Review)
Review
While early coronary reperfusion via primary percutaneous coronary intervention (pPCI) is established as the most efficacious therapy for minimizing infarct size (IS) in acute ST-elevation myocardial infarction (STEMI), the restoration of blood flow also introduces myocardial ischemia-reperfusion injury (IRI), leading to cardiomyocyte death. Among diverse methods, ischemic conditioning (IC), achieved through repetitive cycles of ischemia and reperfusion, has emerged as the most promising method to mitigate IRI. IC can be performed by applying the protective stimulus directly to the affected myocardium or indirectly to non-affected tissue, which is known as remote ischemic conditioning (RIC). In clinical practice, RIC is often applied by serial inflations and deflations of a blood pressure cuff on a limb. Despite encouraging preclinical studies, as well as clinical studies demonstrating reductions in enzymatic IS and myocardial injury on imaging, the observed impact on clinical outcome has been disappointing so far. Nevertheless, previous studies indicate a potential benefit of IC in high-risk STEMI patients. Additional research is needed to evaluate the impact of IC in such high-risk cohorts. The objective of this review is to summarize the pathophysiological background and preclinical and clinical data of IRI reduction by IC.
PubMed: 38202166
DOI: 10.3390/jcm13010159 -
Stroke Dec 2023The Stroke Treatment Academic Industry Roundtable XII included a workshop to discuss the most promising approaches to improve outcome from acute stroke. The workshop... (Review)
Review
The Stroke Treatment Academic Industry Roundtable XII included a workshop to discuss the most promising approaches to improve outcome from acute stroke. The workshop brought together representatives from academia, industry, and government representatives. The discussion examined approaches in 4 epochs: pre-reperfusion, reperfusion, post-reperfusion, and access to acute stroke interventions. The participants identified areas of priority for developing new and existing treatments and approaches to improve stroke outcomes. Although many advances in acute stroke therapy have been achieved, more work is necessary for reperfusion therapies to benefit the most possible patients. Prioritization of promising approaches should help guide the use of resources and investigator efforts.
Topics: Humans; Brain Ischemia; Thrombolytic Therapy; Stroke; Thrombectomy; Reperfusion; Treatment Outcome
PubMed: 37886850
DOI: 10.1161/STROKEAHA.123.044279 -
Biomedicine & Pharmacotherapy =... Sep 2023Renal ischemia-reperfusion injury (RIRI) is a complex disorder characterized by both intrinsic damage to renal tubular epithelial cells and extrinsic inflammation... (Review)
Review
Renal ischemia-reperfusion injury (RIRI) is a complex disorder characterized by both intrinsic damage to renal tubular epithelial cells and extrinsic inflammation mediated by cytokines and immune cells. Unfortunately, there is no cure for this devastating condition. Extracellular vesicles (EVs) are nanosized membrane-bound vesicles secreted by various cell types that can transfer bioactive molecules to target cells and modulate their function. EVs have emerged as promising candidates for cell-free therapy of RIRI, owing to their ability to cross biological barriers and deliver protective signals to injured renal cells. In this review, we provide an overview of EVs, focusing on their functional role in RIRI and the signaling messengers responsible for EV-mediated crosstalk between various cell types in renal tissue. We also discuss the renoprotective role of EVs and their use as therapeutic agents for RIRI, highlighting the advantages and challenges encountered in the therapeutic application of EVs in renal disease.
Topics: Humans; Mesenchymal Stem Cells; Kidney; Reperfusion Injury; Extracellular Vesicles; Acute Kidney Injury
PubMed: 37506581
DOI: 10.1016/j.biopha.2023.115229 -
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 -
Cell Proliferation Jan 2024Neutrophil extracellular trap (NET) has been confirmed to be related to gut barrier injury during intestinal ischaemia-reperfusion (II/R). However, the specific...
Neutrophil extracellular trap (NET) has been confirmed to be related to gut barrier injury during intestinal ischaemia-reperfusion (II/R). However, the specific molecular regulatory mechanism of NETs in II/R-induced intestinal barrier damage has yet to be fully elucidated. Here, we reported increased NETs infiltration accompanied by elevated inflammatory cytokines, cellular necroptosis and tight junction disruption in the intestine of human II/R patients. Meanwhile, NETs aggravated Caco-2 intestinal epithelial cell necroptosis, impairing the monolayer barrier in vitro. Moreover, Pad4-deficient mice were used further to validate the role of NETs in II/R-induced intestinal injury. In contrast, NET inhibition via Pad4 deficiency alleviated intestinal inflammation, attenuated cellular necroptosis, improved intestinal permeability, and enhanced tight junction protein expression. Notably, NETs prevented FUN14 domain-containing 1 (FUNDC1)-required mitophagy activation in intestinal epithelial cells, and stimulating mitophagy attenuated NET-associated mitochondrial dysfunction, cellular necroptosis, and intestinal damage. Mechanistically, silencing Toll-like receptor 4 (TLR4) or receptor-interacting protein kinase 3 (RIPK3) via shRNA relieved mitophagy limitation, restored mitochondrial function and reduced NET-induced necroptosis in Caco-2 cells, whereas this protective effect was reversed by TLR4 or RIPK3 overexpression. The regulation of TLR4/RIPK3/FUNDC1-required mitophagy by NETs can potentially induce intestinal epithelium necroptosis.
Topics: Humans; Mice; Animals; Caco-2 Cells; Extracellular Traps; Toll-Like Receptor 4; Necroptosis; Mitophagy; Reperfusion Injury; Ischemia; Reperfusion; Receptor-Interacting Protein Serine-Threonine Kinases; Membrane Proteins; Mitochondrial Proteins
PubMed: 37691112
DOI: 10.1111/cpr.13538 -
Arquivos de Neuro-psiquiatria Dec 2023Over the last three decades, stroke care has undergone significant transformations mainly driven by the introduction of reperfusion therapy and the organization of... (Review)
Review
Over the last three decades, stroke care has undergone significant transformations mainly driven by the introduction of reperfusion therapy and the organization of systems of care. Patients receiving treatment through a well-structured stroke service have a much higher chance of favorable outcomes, thereby decreasing both disability and mortality. In this article, we reviewed the scientific evidence for stroke reperfusion therapy, including thrombolysis and thrombectomy, and its implementation in the public health system in Brazil.
Topics: Humans; Ischemic Stroke; Brain Ischemia; Stroke; Thrombectomy; Thrombolytic Therapy; Reperfusion; Treatment Outcome
PubMed: 38157871
DOI: 10.1055/s-0043-1777721 -
International Immunopharmacology Jul 2023Ferroptosis is involved in ischemia and reperfusion injury (IRI) of transplanted kidney. Understanding the molecular mechanisms of ferroptosis is essential to elucidate...
Ferroptosis is involved in ischemia and reperfusion injury (IRI) of transplanted kidney. Understanding the molecular mechanisms of ferroptosis is essential to elucidate the pathogenesis of IRI. 1307 differentially expressed genes (DEGs) were obtained by GSE90861 retrieved from the GEO database. 29 ferroptosis-related DEGs were obtained from the intersection with FerrDb database, which were subjected to enrichment analysis and cytoHubba plugin for selecting the top three (IL6, ATF3 and JUN) as hub genes. Next, ROC analysis of hub genes showed good diagnostic prospects in both GSE90861 and GSE126805. Given the close link between ferroptosis and immunity, immunological analysis of CIBERSORTx revealed that the proportions of 10 cell types out of 22 immune cells in the transplanted kidney significantly changed after reperfusion. To study the relationship between IRI and ferroptosis, 15 male C57BL/6j mice were randomly divided into three groups: control (C), ischemia and reperfusion (IR), and IR + Fer-1 (IF) groups. The IRI mouse model not only developed significant histological damage changes, but also exhibited mitochondrial damage, iron accumulation, increased MDA, and decreased GSH. The ferroptosis inhibitor, Fer-1, ameliorated renal IRI, as demonstrated by rise of GPX4 and decline of TFRC, PTGS2 and ACSL4. In addition, hub genes were further confirmed by significant increase in IRI mouse model the same as the GEO database. In brief, ferroptosis-related hub genes (IL-6, ATF3 and JUN) screened were closely relevant to immune response and might be diagnostic biomarkers and therapeutic targets for IRI during renal transplantation, which could prevent renal allograft dysfunction.
Topics: Mice; Animals; Male; Kidney Transplantation; Ferroptosis; Mice, Inbred C57BL; Kidney; Reperfusion Injury; Disease Models, Animal
PubMed: 37279643
DOI: 10.1016/j.intimp.2023.110393 -
Pharmaceutics Nov 2023Ischemic stroke is a leading cause of death and disability in the world. At present, reperfusion therapy and neuroprotective therapy, as guidelines for identifying... (Review)
Review
Ischemic stroke is a leading cause of death and disability in the world. At present, reperfusion therapy and neuroprotective therapy, as guidelines for identifying effective and adjuvant treatment methods, are limited by treatment time windows, drug bioavailability, and side effects. Nanomaterial-based drug delivery systems have the characteristics of extending half-life, increasing bioavailability, targeting drug delivery, controllable drug release, and low toxicity, thus being used in the treatment of ischemic stroke to increase the therapeutic effects of drugs. Therefore, this review provides a comprehensive overview of nanomaterial-based drug delivery systems from nanocarriers, targeting ligands and stimulus factors of drug release, aiming to find the best combination of nanomaterial-based drug delivery systems for ischemic stroke. Finally, future research areas on nanomaterial-based drug delivery systems in ischemic stroke and the implications of the current knowledge for the development of novel treatment for ischemic stroke were identified.
PubMed: 38140010
DOI: 10.3390/pharmaceutics15122669 -
Biomedicine & Pharmacotherapy =... Dec 2023Hepatic ischemia-reperfusion injury (HIRI) adversely affects liver transplant and resection outcomes. Recently, ferroptosis has been associated with HIRI....
Hepatic ischemia-reperfusion injury (HIRI) adversely affects liver transplant and resection outcomes. Recently, ferroptosis has been associated with HIRI. Dexmedetomidine (Dex), a potent sedative with anti-inflammatory, antioxidant, and anti-apoptotic properties, protects organs from hypoxic or ischemia-reperfusion (I/R) injuries. However, the mechanisms underlying this protective effect against I/R-induced liver injury remain unclear. This study evaluated the effect of Dex on HIRI in mouse models and the oxygen-glucose deprivation/reperfusion (OGD/R) AML12 cell model. We examined ferroptosis-related markers, including Fe levels, reactive oxygen species (ROS) content, mitochondrial morphology, GPX4 protein expression, 4-hydroxynonenal (4-HNE), and Nrf2. The Nrf2 inhibitor ML385 was used in combination with Dex to treat HIRI mice and OGD/R-induced cellular models to explore the pathways by which Dex counteracts ferroptosis. Our results showed that Dex treatment significantly ameliorated OGD/R-induced ferroptosis in AML12 cells, including reduced Fe, ROS, malondialdehyde (MDA), and 4-HNE levels. Dex also ameliorated liver tissue damage and reduced serum AST, ALT, and inflammatory factor levels in HIRI mice. Additionally, Dex increased the levels of GSH, an antioxidative stress marker, and GPX4 expression in HIRI mice. Mechanistically, Nrf2 expression and nuclear translocation were significantly inhibited in both HIRI mice and OGD/R-treated AML12 cells. Dex treatment also restored the I/R-induced inhibition of Nrf2 expression and nuclear translocation. ML385 significantly inhibited Dex-promoted Nrf2 nuclear aggregation with Gpx4 protein expression, hindering the efficacy of Dex. In conclusion, Dex ameliorates ferroptosis in HIRI by positively regulating the Nrf2/GPx4 axis, potentially presenting a therapeutic avenue for addressing HIRI.
Topics: Animals; Mice; Antioxidants; Dexmedetomidine; NF-E2-Related Factor 2; Ferroptosis; Reactive Oxygen Species; Liver; Reperfusion Injury
PubMed: 38000361
DOI: 10.1016/j.biopha.2023.115915