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Annals of Clinical and Translational... Nov 2023This study aimed to investigate whether treatment with adjunct intravenous tirofiban is associated with improved outcomes following successful reperfusion in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
This study aimed to investigate whether treatment with adjunct intravenous tirofiban is associated with improved outcomes following successful reperfusion in patients with intracranial atherosclerotic stroke.
METHODS
Patients with intracranial large artery atherosclerotic (LAA) stroke and an expanded Treatment in Cerebral Ischemia angiographic score of 2b50 to 3 from the Effect of Intravenous Tirofiban versus Placebo Before Endovascular Thrombectomy on Functional Outcomes in Large Vessel Occlusion Stroke (RESCUE BT) trial were included. The primary outcome was the difference in proportion of independent functional outcome (modified Rankin score of 0-2 at 90 days). Safety outcomes included the rates of symptomatic intracranial hemorrhage (sICH) and 90-day mortality.
RESULTS
Among the 382 patients with intracranial LAA stroke and successful reperfusion, 175 patients (45.8%) were treated with intravenous tirofiban and 207 (54.2%) with placebo. The proportion of patients with independent functional outcome at 90 days was 54.3% (95 out of 175) with tirofiban and 44.0% (91 out of 207) with placebo (adjusted odds ratio [aOR], 1.58; 95% CI, 1.02-2.44; p = 0.04). Intravenous tirofiban was not significantly associated with an increased risk of sICH (12/175 [6.9%] vs. 11/207 [5.3%]; aOR, 1.41; 95% CI, 0.59-3.34; p = 0.44) or 90-day mortality (21/175 [12.0%] vs. 34/207 [16.4%]; aOR, 0.71; 95% CI, 0.38-1.31; p = 0.27).
INTERPRETATION
Among patients with acute intracranial LAA stroke and successful reperfusion following endovascular thrombectomy, adjunct intravenous tirofiban was associated with a higher rate of independent functional outcome, without higher rates of sICH or mortality. Confirmatory randomized trials in these patients are desirable.
Topics: Humans; Tirofiban; Fibrinolytic Agents; Brain Ischemia; Treatment Outcome; Stroke; Intracranial Hemorrhages; Arteries; Reperfusion
PubMed: 37649303
DOI: 10.1002/acn3.51891 -
Free Radical Biology & Medicine Aug 2023Ischemia-reperfusion injury is a critical liver condition during hepatic transplantation, trauma, or shock. An ischemic deprivation of antioxidants and energy...
Ischemia-reperfusion injury is a critical liver condition during hepatic transplantation, trauma, or shock. An ischemic deprivation of antioxidants and energy characterizes liver injury in such cases. In the face of increased reactive oxygen production, hepatocytes are vulnerable to the reperfusion driving ROS generation and multiple cell-death mechanisms. In this study, we investigate the importance of hydrogen sulfide as part of the liver's antioxidant pool and the therapeutic potency of the hydrogen sulfide donors sodium sulfide (NaS, fast releasing) and sodium thiosulfate (STS, NaSO, slow releasing). The mitoprotection and toxicity of STS and NaS were investigated on isolated mitochondria and a liver perfusion oxidative stress model by adding text-butyl hydroperoxide and hydrogen sulfide donors. The respiratory capacity of mitochondria, hepatocellular released LDH, glutathione, and lipid-peroxide levels were quantified. In addition, wild-type and cystathionine-γ-lyase knockout mice were subjected to warm selective ischemia-reperfusion injury by clamping the main inflow for 1 h followed by reperfusion of 1 or 24 h. A subset of animals was treated with STS shortly before reperfusion. Glutathione, plasma ALT, and lipid-peroxide levels were investigated alongside mitochondrial changes in structure (electron microscopy) and function (intravital microscopy). Liver tissue necrosis quantified 24 h after reperfusion indicates the net effects of the treatment on the organ. STS refuels and protects the endogenous antioxidant pool during liver ischemia-reperfusion injury. In addition, STS-mediated ROS scavenging significantly reduced lipid peroxidation and mitochondrial damage, resulting in better molecular and histopathological preservation of the liver tissue architecture. STS prevents tissue damage in liver ischemia-reperfusion injury by increasing the liver's antioxidant pool, thereby protecting mitochondrial integrity.
Topics: Mice; Animals; Antioxidants; Hydrogen Sulfide; Reactive Oxygen Species; Chemical and Drug Induced Liver Injury, Chronic; Liver; Reperfusion Injury; Ischemia; Glutathione; Peroxides; Reperfusion; Lipids
PubMed: 37105418
DOI: 10.1016/j.freeradbiomed.2023.04.012 -
Redox Biology Nov 2023Adenosine kinase (ADK) plays the major role in cardiac adenosine metabolism, so that inhibition of ADK increases myocardial adenosine levels. While the cardioprotective...
Adenosine kinase (ADK) plays the major role in cardiac adenosine metabolism, so that inhibition of ADK increases myocardial adenosine levels. While the cardioprotective actions of extracellular adenosine against ischemia/reperfusion (I/R) are well-established, the role of cellular adenosine in protection against I/R remains unknown. Here we investigated the role of cellular adenosine in epigenetic regulation on cardiomyocyte gene expression, glucose metabolism and tolerance to I/R. Evans blue/TTC staining and echocardiography were used to assess the extent of I/R injury in mice. Glucose metabolism was evaluated by positron emission tomography and computed tomography (PET/CT). Methylated DNA immunoprecipitation (MeDIP) and bisulfite sequencing PCR (BSP) were used to evaluate DNA methylation. Lentiviral/adenovirus transduction was used to overexpress DNMT1, and the OSI-906 was administered to inhibit IGF-1. Cardiomyocyte-specific ADK/IGF-1-knockout mice were used for mechanistic experiments.Cardiomyocyte-specific ADK knockout enhanced glucose metabolism and ameliorated myocardial I/R injury in vivo. Mechanistically, ADK deletion caused cellular adenosine accumulation, decreased DNA methyltransferase 1 (DNMT1) expression and caused hypomethylation of multiple metabolic genes, including insulin growth factor 1 (IGF-1). DNMT1 overexpression abrogated these beneficial effects by enhancing apoptosis and decreasing IGF-1 expression. Inhibition of IGF-1 signaling with OSI-906 or genetic knocking down of IGF-1 also abrogated the cardioprotective effects of ADK knockout, revealing the therapeutic potential of increasing IGF-1 expression in attenuating myocardial I/R injury. In conclusion, the present study demonstrated that cardiomyocyte ADK deletion ameliorates myocardial I/R injury via epigenetic upregulation of IGF-1 expression via the cardiomyocyte adenosine/DNMT1/IGF-1 axis.
Topics: Mice; Animals; Myocytes, Cardiac; Epigenesis, Genetic; Adenosine; Insulin-Like Growth Factor I; Positron Emission Tomography Computed Tomography; Ischemia; Myocardial Reperfusion Injury; Mice, Knockout; Apoptosis; Reperfusion; DNA; Glucose
PubMed: 37725888
DOI: 10.1016/j.redox.2023.102884 -
Materia Socio-medica 2024Acute mesenteric ishemia(AMI) is a rare but very serious disease with high rate of mortality and morbidity. About 1-2% of all gastrointestinal disease is AMI. Mortality... (Review)
Review
BACKGROUND
Acute mesenteric ishemia(AMI) is a rare but very serious disease with high rate of mortality and morbidity. About 1-2% of all gastrointestinal disease is AMI. Mortality is about 60-80% and depends of time between starting of symptoms and establishing of diagnosis, type AMI, comorbidities. AMI is often in older population with coronary syndrom and atrial fibrilation. AMI may be occlusive(embolisatio arteriae mesentericae superior(AMS), or thrombosis of AMS, mesenterial vein thrombosis) and nonoclusive form(NOMI). NOMI is rising in critical ill patients in shock or sepsis. Pathophysiology of AMI is very complex and significant role in this proces has ischemia and also reperfusion. Reperfusion injury including oxidative stres, inflamation, infection. The best diagnostic approach is CT angiography but after high clinical suspicion on AMI. Patients have sudden, catastrophic abdominal pain, vomitus, bloody diarrhoea. Therapy is multidisciplinary-basic treatment(resuscitation with cristaloids, antibiotic, anticoagulans...), surgical treatment-resection necrotic segments of intestinum without anastomosis or endovascular treatment. In early phases conservative treatment is possible( vasodilatation, thrombolysis). In some countries there are Intestinal Stroke Centers (ISC) in which patients with AMI have better prognosis. Because of progressive nature of AMI( rapide worsening) rare are clinical study,but there are many experimental study on animal models. Most of experimental study investigate protective effects of some supstances on damage on intestinum and remote organs during ishemia and reperfusion.
OBJECTIVE
To present literature data of clinical and experimental study, describe experiments on animal models and mention supstances whit promising results in protective strategies during AMI.
METHODS
We analysed Pubmed by using mesh terms such as acute mesenteric ischemia, intestinal injury, reperfusion, experimental study, clinical and therapeutic approach. Results: Sudden abdominal pain resists on opioids analgetics, high rate of CRP, hyperlactatemia, increase of D dimer is enough for suspicion of AMI. Often is delayed in establishing of diagnosis of AMI. CT angiography has sensitivity of 94%. Pneumatosis is sign of necrosis of intestinal wall. Classical surgical approach is dominant, more than 70%,. Endovascular treatment became often last few years. Experimental studies investigate occlusion of AMS with atraumatic clamp, with schemia and reperfusion in different intervals Most animals models are on wistar male rats.
CONCLUSION
AMI has still high rate of mortality. Better diagnostic and therapeutic principles (shorter interval between appearance of symptoms and starting of therapy, multidisciplinary approach, higher percent of endovascular procedures), could decrease mortality. Experimental studies on animal models may be succesfull in development of new clinical, conservative approaches in the early phases of AMI in the future.
PubMed: 38590590
DOI: 10.5455/msm.2024.36.77-81 -
Cell Communication and Signaling : CCS Aug 2023Acute myocardial infarction has long been the leading cause of death in coronary heart disease, which is characterized by irreversible cardiomyocyte death and restricted... (Review)
Review
Acute myocardial infarction has long been the leading cause of death in coronary heart disease, which is characterized by irreversible cardiomyocyte death and restricted blood supply. Conventional reperfusion therapy can further aggravate myocardial injury. Stem cell therapy, especially with mesenchymal stem cells (MSCs), has emerged as a promising approach to promote cardiac repair and improve cardiac function. MSCs may induce these effects by secreting exosomes containing therapeutically active RNA, proteins and lipids. Notably, normal cardiac function depends on intracardiac paracrine signaling via exosomes, and exosomes secreted by cardiac cells can partially reflect changes in the heart during disease, so analyzing these vesicles may provide valuable insights into the pathology of myocardial infarction as well as guide the development of new treatments. The present review examines how exosomes produced by MSCs and cardiac cells may influence injury after myocardial infarction and serve as therapies against such injury. Video Abstract.
Topics: Humans; Exosomes; Apoptosis; Myocardial Infarction; Myocytes, Cardiac; Mesenchymal Stem Cells
PubMed: 37580705
DOI: 10.1186/s12964-023-01227-9 -
Brain Circulation 2024Acute ischemic stroke (AIS) remains to be a challenging cerebrovascular disease. The mainstay of AIS management is endovascular reperfusion therapy, including...
Acute ischemic stroke (AIS) remains to be a challenging cerebrovascular disease. The mainstay of AIS management is endovascular reperfusion therapy, including thrombectomy and thrombolysis. However, ineffective (futile) reperfusion (FR) or reperfusion injury (RI) can be seen in a significant number of patients undergoing reperfusion strategy. In this article, we discuss two clinically relevant concepts known as "time window" and "tissue window" that can impact the clinical outcome of reperfusion therapy. We also explore patient risk factors, leading to FR and RI as well as an emerging concept of "no-reflow phenomenon" seen in ineffective reperfusion. These fundamental concepts provide insight into the clinical management of AIS patients and provide references for future research.
PubMed: 38655438
DOI: 10.4103/bc.bc_9_24 -
Brain Sciences Sep 2023A disruption of the blood-brain barrier (BBB) is a crucial pathophysiological change that can impact the outcome of a stroke. Ribosomal protein S6 (S6) and protein...
A disruption of the blood-brain barrier (BBB) is a crucial pathophysiological change that can impact the outcome of a stroke. Ribosomal protein S6 (S6) and protein kinase B (Akt) play significant roles in early cerebral ischemia-reperfusion injury. Studies have suggested that branched-chain amino acids (BCAAs) may have neuroprotective properties for spinal cord or brain injuries. Therefore, we conducted research to investigate if leucine, one of the BCAAs, could offer neuroprotection and alter BBB disruption, along with its effects on the phosphorylation of S6 and Akt during the early phase of cerebral ischemia-reperfusion, specifically within the thrombolytic therapy time window. In rats, ten min after left middle cerebral artery occlusion (MCAO), 5 µL of 20 mM L-leucine or normal saline was injected into the left lateral ventricle. After two hours of reperfusion following one hour of MCAO, we determined the transfer coefficient (K) of C-α-aminoisobutyric acid to assess the BBB disruption, infarct size, and phosphorylation of S6 and Akt. Ischemia-reperfusion increased the K (+143%, < 0.001) and the intra-cerebroventricular injection of leucine lowered the K in the ischemic-reperfused cortex (-34%, < 0.001). Leucine reduced the percentage of cortical infarct (-42%, < 0.0001) out of the total cortical area. Ischemia-reperfusion alone significantly increased the phosphorylation of both S6 and Akt ( < 0.05). However, the administration of leucine had no further effect on the phosphorylation of S6 or Akt in the ischemic-reperfused cortex. This study suggests that an acute increase in leucine levels in the brain during early ischemia-reperfusion within a few hours of stroke may offer neuroprotection, possibly due to reduced BBB disruption being one of the major contributing factors. Leucine did not further increase the already elevated phosphorylation of S6 or Akt by ischemia-reperfusion under the current experimental conditions. Our data warrant further studies on the effects of leucine on neuronal survival and its mechanisms in the later stages of cerebral ischemia-reperfusion.
PubMed: 37891741
DOI: 10.3390/brainsci13101372 -
Life Sciences Mar 2024Myocardial ischemia-reperfusion injury (MIRI), caused by the initial interruption and subsequent restoration of coronary artery blood, results in further damage to... (Review)
Review
Myocardial ischemia-reperfusion injury (MIRI), caused by the initial interruption and subsequent restoration of coronary artery blood, results in further damage to cardiac function, affecting the prognosis of patients with acute myocardial infarction. Ferroptosis is an iron-dependent, superoxide-driven, non-apoptotic form of regulated cell death that is involved in the pathogenesis of MIRI. Ferroptosis is characterized by the accumulation of lipid peroxides (LOOH) and redox disequilibrium. Free iron ions can induce lipid oxidative stress as a substrate of the Fenton reaction and lipoxygenase (LOX) and participate in the inactivation of a variety of lipid antioxidants including CoQ10 and GPX4, destroying the redox balance and causing cell death. The metabolism of amino acid, iron, and lipids, including associated pathways, is considered as a specific hallmark of ferroptosis. This review systematically summarizes the latest research progress on the mechanisms of ferroptosis and discusses and analyzes the therapeutic approaches targeting ferroptosis to alleviate MIRI.
Topics: Humans; Ferroptosis; Myocardial Reperfusion Injury; Amino Acids; Iron; Lipid Peroxides; Reperfusion Injury
PubMed: 38278348
DOI: 10.1016/j.lfs.2024.122439 -
JCI Insight Mar 2024Efficient clearance and degradation of apoptotic cardiomyocytes by macrophages (collectively termed efferocytosis) is critical for inflammation resolution and...
Efficient clearance and degradation of apoptotic cardiomyocytes by macrophages (collectively termed efferocytosis) is critical for inflammation resolution and restoration of cardiac function after myocardial ischemia/reperfusion (I/R). Here, we define secreted and transmembrane protein 1a (Sectm1a), a cardiac macrophage-enriched gene, as a modulator of macrophage efferocytosis in I/R-injured hearts. Upon myocardial I/R, Sectm1a-KO mice exhibited impaired macrophage efferocytosis, leading to massive accumulation of apoptotic cardiomyocytes, cardiac inflammation, fibrosis, and consequently, exaggerated cardiac dysfunction. By contrast, therapeutic administration of recombinant SECTM1A protein significantly enhanced macrophage efferocytosis and improved cardiac function. Mechanistically, SECTM1A could elicit autocrine effects on the activation of glucocorticoid-induced TNF receptor (GITR) at the surface of macrophages, leading to the upregulation of liver X receptor α (LXRα) and its downstream efferocytosis-related genes and lysosomal enzyme genes. Our study suggests that Sectm1a-mediated activation of the Gitr/LXRα axis could be a promising approach to enhance macrophage efferocytosis for the treatment of myocardial I/R injury.
Topics: Mice; Animals; Phagocytosis; Efferocytosis; Apoptosis; Macrophages; Inflammation; Membrane Proteins; Myocardial Reperfusion Injury; Reperfusion
PubMed: 38456501
DOI: 10.1172/jci.insight.173832 -
IScience Sep 2023Morbidity and mortality caused by acute myocardial infarction (AMI) are on the rise, posing a grave threat to the health of the general population. Up to now,... (Review)
Review
Morbidity and mortality caused by acute myocardial infarction (AMI) are on the rise, posing a grave threat to the health of the general population. Up to now, interventional, surgical, and pharmaceutical therapies have been the main treatment methods for AMI. Effective and timely reperfusion therapy decreases mortality, but it cannot stimulate myocardial cell regeneration or reverse ventricular remodeling. Cell therapy, gene therapy, immunotherapy, anti-inflammatory therapy, and several other techniques are utilized by researchers to improve patients' prognosis. In recent years, biomaterials for AMI therapy have become a hot spot in medical care. Biomaterials furnish a microenvironment conducive to cell growth and deliver therapeutic factors that stimulate cell regeneration and differentiation. Biomaterials adapt to the complex microenvironment and respond to changes in local physical and biochemical conditions. Therefore, environmental factors and material properties must be taken into account when designing biomaterials for the treatment of AMI. This article will review the factors that need to be fully considered in the design of biological materials.
PubMed: 37670787
DOI: 10.1016/j.isci.2023.107662